Parkinson's disease as a result of aging

Aging Cell

Volumn 14, Issue 3, 2015, Pages 293-308

  Rodriguez, Manuel ^a,b   Rodriguez Sabate, Clara ^b   Morales, Ingrid ^a,b   Sanchez, Alberto ^a   Sabate, Magdalena ^a  

^a UNIVERSIDAD DE LA LAGUNA   (Spain)

^b CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

Author keywords

Aging; Dopamine; Neurodegeneration; Nigrostriatal neurons; Parkinson's disease

Indexed keywords

AGING; CELL POPULATION; DOPAMINERGIC NERVE CELL; HUMAN; MITOCHONDRION; NERVE DEGENERATION; NONMYELINATED NERVE; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW; SENESCENCE; SYNAPTIC MEMBRANE; ANIMAL; BRAIN; METABOLISM; NERVE CELL; PHYSIOLOGY;

DOPAMINE;

AGING; ANIMALS; BRAIN; DOPAMINE; HUMANS; MITOCHONDRIA; NEURONS; PARKINSON DISEASE;

EID: 84927911413     PISSN: 14749718     EISSN: 14749726     Source Type: Journal    
DOI: 10.1111/acel.12312     Document Type: Review

References (388)

1. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252.
2. Ahlskog JE (2005) Challenging conventional wisdom: the etiologic role of dopamine oxidative stress in Parkinson's disease. Mov. Disord. 20, 271-282.
3. Albanese A, Valente EM, Romito LM, Bellacchio E, Elia AE, Dallapiccola B (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64, 1958-1960.
4. Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro A, Forloni G (2009) The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J. Neurochem. 110, 1445-1456.
5. Allen NJ, Barres BA (2009) Neuroscience: Glia - more than just brain glue. Nature 457, 675-677.
6. Alonso J, Castellano MA, Rodriguez M (1991a) Behavioral lateralization in rats: prenatal stress effects on sex differences. Brain Res. 539, 45-50.
7. Alonso SJ, Castellano MA, Afonso D, Rodriguez M (1991b) Sex differences in behavioral despair: relationships between behavioral despair and open field activity. Physiol. Behav. 49, 69-72.
8. Alvira D, Yeste-Velasco M, Folch J, Verdaguer E, Canudas AM, Pallas M, Camins A (2007) Comparative analysis of the effects of resveratrol in two apoptotic models: inhibition of complex I and potassium deprivation in cerebellar neurons. Neuroscience 147, 746-756.
9. Ameur A, Stewart JB, Freyer C, Hagstrom E, Ingman M, Larsson NG, Gyllensten U (2011) Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028.
10. Amiri M, Hollenbeck PJ (2008) Mitochondrial biogenesis in the axons of vertebrate peripheral neurons. Dev. Neurobiol. 68, 1348-1361.
11. Arango V, Underwood MD, Pauler DK, Kass RE, Mann JJ (1996) Differential age-related loss of pigmented locus coeruleus neurons in suicides, alcoholics, and alcoholic suicides. Alcohol. Clin. Exp. Res. 20, 1141-1147.
12. Arevalo R, Afonso D, Castro R, Rodriguez M (1991) Fetal brain serotonin synthesis and catabolism is under control by mother intake of tryptophan. Life Sci. 49, 53-66.
13. Asanuma M, Hirata H, Cadet JL (1998) Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice. Neuroscience 85, 907-917.
14. Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, Barzilai N (2004) Clinical phenotype of families with longevity. J. Am. Geriatr. Soc. 52, 274-277.
15. Austad SN (2004) Is aging programed? Aging Cell 3, 249-251.
16. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008) Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell 7, 13-22.
17. Bai XY, Ma Y, Ding R, Fu B, Shi S, Chen XM (2011) miR-335 and miR-34a Promote renal senescence by suppressing mitochondrial antioxidative enzymes. J. Am. Soc. Nephrol. 22, 1252-1261.
18. Baker KG, Tork I, Hornung JP, Halasz P (1989) The human locus coeruleus complex: an immunohistochemical and three dimensional reconstruction study. Exp. Brain Res. 77, 257-270.
19. Ballard PA, Tetrud JW, Langston JW (1985) Permanent human parkinsonism due to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP): seven cases. Neurology 35, 949-956.
20. Bandiera S, Ruberg S, Girard M, Cagnard N, Hanein S, Chretien D, Munnich A, Lyonnet S, Henrion-Caude A (2011) Nuclear outsourcing of RNA interference components to human mitochondria. PLoS ONE 6, e20746.
21. Barcia C, Sanchez Bahillo A, Fernandez-Villalba E, Bautista V, Poza YPM, Fernandez-Barreiro A, Hirsch EC, Herrero MT (2004) Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure. Glia 46, 402-409.
22. Barja G (2002a) Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res. Rev. 1, 397-411.
23. Barja G (2002b) Rate of generation of oxidative stress-related damage and animal longevity. Free Radic. Biol. Med. 33, 1167-1172.
24. Barja G, Herrero A (2000) Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. Faseb J. 14, 312-318.
25. Barrio JR, Huang SC, Melega WP, Yu DC, Hoffman JM, Schneider JS, Satyamurthy N, Mazziotta JC, Phelps ME (1990) 6-[18F]fluoro-L-dopa probes dopamine turnover rates in central dopaminergic structures. J. Neurosci. Res. 27, 487-493.
26. Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochim. Biophys. Acta 1366, 211-223.
27. Belanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab. 14, 724-738.
28. Bellinger FP, Bellinger MT, Seale LA, Takemoto AS, Raman AV, Miki T, Manning-Bog AB, Berry MJ, White LR, Ross GW (2011) Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain. Mol. Neurodegener. 6, 8.
29. Benarroch EE (2009) Astrocyte-neuron interactions: implications for epilepsy. Neurology 73, 1323-1327.
30. Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515-517.
31. Berg D, Hochstrasser H (2006) Iron metabolism in Parkinsonian syndromes. Mov. Disord. 21, 1299-1310.
32. Bertrand E, Lechowicz W, Szpak GM, Dymecki J (1997) Qualitative and quantitative analysis of locus coeruleus neurons in Parkinson's disease. Folia Neuropathol. 35, 80-86.
33. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301-1306.
34. Bokov A, Chaudhuri A, Richardson A (2004) The role of oxidative damage and stress in aging. Mech. Ageing Dev. 125, 811-826.
35. Bonifati V, Rizzu P, Squitieri F, Krieger E, Vanacore N, van Swieten JC, Brice A, van Duijn CM, Oostra B, Meco G, Heutink P (2003a) DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol. Sci. 24, 159-160.
36. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P (2003b) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256-259.
37. Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA (1999) Mitochondrial involvement in Alzheimer's disease. Biochim. Biophys. Acta 1410, 171-182.
38. Boore JL (1999) Animal mitochondrial genomes. Nucleic Acids Res. 27, 1767-1780.
39. Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, Wentworth P Jr, Lerner RA, Kelly JW (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat. Chem. Biol. 2, 249-253.
40. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat. Med. 10(Suppl), S2-S9.
41. Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J. Neurol. 249(Suppl 3), III/1-5.
42. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197-211.
43. Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K (2006) Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov. Disord. 21, 2042-2051.
44. Braak H, Sastre M, Del Tredici K (2007) Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathol. 114, 231-241.
45. Brack C, Lithgow G, Osiewacz H, Toussaint O (2000) EMBO WORKSHOP REPORT: molecular and cellular gerontology Serpiano, Switzerland, September 18-22, 1999. EMBO J. 19, 1929-1934.
46. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love-hate triangle. Am. J. Physiol. Cell Physiol. 287, C817-C833.
47. Buchman AS, Shulman JM, Nag S, Leurgans SE, Arnold SE, Morris MC, Schneider JA, Bennett DA (2012) Nigral pathology and parkinsonian signs in elders without Parkinson disease. Ann. Neurol. 71, 258-266.
48. Budovsky A, Craig T, Wang J, Tacutu R, Csordas A, Lourenco J, Fraifeld VE, de Magalhaes JP (2013) LongevityMap: a database of human genetic variants associated with longevity. Trends Genet. 29, 559-560.
49. Bueler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease. Exp. Neurol. 218, 235-246.
50. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc. Natl Acad. Sci. USA 80, 4546-4550.
51. Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B (2002) Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol. Appl. Neurobiol. 28, 283-291.
52. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F (2014) The search for antiaging interventions: from elixirs to fasting regimens. Cell 157, 1515-1526.
53. Cai Z, Fan LW, Kaizaki A, Tien LT, Ma T, Pang Y, Lin S, Lin RC, Simpson KL (2012) Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Dev. Neurosci. 35, 155-171.
54. Cakatay U, Telci A, Kayali R, Tekeli F, Akcay T, Sivas A (2003) Relation of aging with oxidative protein damage parameters in the rat skeletal muscle. Clin. Biochem. 36, 51-55.
55. Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J. Neurosci. Res. 87, 2484-2497.
56. Cantuti-Castelvetri I, Lin MT, Zheng K, Keller-McGandy CE, Betensky RA, Johns DR, Beal MF, Standaert DG, Simon DK (2005) Somatic mitochondrial DNA mutations in single neurons and glia. Neurobiol. Aging 26, 1343-1355.
57. Carlsson A, Winblad B (1976) Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J. Neural. Transm. 38, 271-276.
58. Carvey PM, Chang Q, Lipton JW, Ling Z (2003) Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring: a potential, new model of Parkinson's disease. Front. Biosci. 8, s826-s837.
59. Centonze D, Grande C, Saulle E, Martin AB, Gubellini P, Pavon N, Pisani A, Bernardi G, Moratalla R, Calabresi P (2003) Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity. J. Neurosci. 23, 8506-8512.
60. Cersosimo MG, Benarroch EE (2011) Pathological correlates of gastrointestinal dysfunction in Parkinson's disease. Neurobiol. Dis. 46, 559-564.
61. Chao J, Yu MS, Ho YS, Wang M, Chang RC (2008) Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic. Biol. Med. 45, 1019-1026.
62. Cheng HC, Ulane CM, Burke RE (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715-725.
63. Cheng HC, Kim SR, Oo TF, Kareva T, Yarygina O, Rzhetskaya M, Wang C, During M, Talloczy Z, Tanaka K, Komatsu M, Kobayashi K, Okano H, Kholodilov N, Burke RE (2011) Akt suppresses retrograde degeneration of dopaminergic axons by inhibition of macroautophagy. J. Neurosci. 31, 2125-2135.
64. Chinnery PF, Howell N, Andrews RM, Turnbull DM (1999) Mitochondrial DNA analysis: polymorphisms and pathogenicity. J. Med. Genet. 36, 505-510.
65. Chinta SJ, Lieu CA, Demaria M, Laberge RM, Campisi J, Andersen JK (2013) Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease? J. Intern. Med. 273, 429-436.
66. Chu Y, Le W, Kompoliti K, Jankovic J, Mufson EJ, Kordower JH (2006) Nurr1 in Parkinson's disease and related disorders. J. Comp. Neurol. 494, 495-514.
67. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res. Rev. 8, 18-30.
68. Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat. Rev. Neurosci. 6, 889-898.
69. Collier TJ, Kanaan NM, Kordower JH (2011) Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat. Rev. Neurosci. 12, 359-366.
70. Conley KE, Amara CE, Jubrias SA, Marcinek DJ (2007) Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo. Exp. Physiol. 92, 333-339.
71. Conover JC, Shook BA (2011) Aging of the Subventricular Zone Neural Stem Cell Niche. Aging Dis. 2, 149-163.
72. Coon S, Stark A, Peterson E, Gloi A, Kortsha G, Pounds J, Chettle D, Gorell J (2006) Whole-body lifetime occupational lead exposure and risk of Parkinson's disease. Environ. Health Perspect. 114, 1872-1876.
73. Court FA, Coleman MP (2012) Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci. 35, 364-372.
74. Croisier E, Moran LB, Dexter DT, Pearce RK, Graeber MB (2005) Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J. Neuroinflammation 2, 14.
75. Cruz-Muros I, Afonso-Oramas D, Abreu P, Barroso-Chinea P, Rodriguez M, Gonzalez MC, Hernandez TG (2007a) Aging of the rat mesostriatal system: differences between the nigrostriatal and the mesolimbic compartments. Exp. Neurol. 204, 147-161.
76. Cruz-Muros I, Afonso-Oramas D, Abreu P, Barroso-Chinea P, Rodriguez M, Gonzalez MC, Hernandez TG (2008) Deglycosylation and subcellular redistribution of VMAT2 in the mesostriatal system during normal aging. Neurobiol. Aging 29, 1702-1711.
77. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295.
78. Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71-90.
79. Dai Y, Kiselak T, Clark J, Clore E, Zheng K, Cheng A, Kujoth GC, Prolla TA, Maratos-Flier E, Simon DK (2013) Behavioral and metabolic characterization of heterozygous and homozygous POLG mutator mice. Mitochondrion 13, 282-291.
80. Damier P, Hirsch EC, Zhang P, Agid Y, Javoy-Agid F (1993) Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52, 1-6.
81. Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 122(Pt 8), 1437-1448.
82. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752-758.
83. Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819-822.
84. De La Hera DP, Corradi GR, Adamo HP, De Tezanos Pinto F (2013) Parkinson's disease-associated human P5B-ATPase ATP13A2 increases spermidine uptake. Biochem. J. 450, 47-53.
85. De Vos KJ, Grierson AJ, Ackerley S, Miller CC (2008) Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151-173.
86. Deierborg T, Soulet D, Roybon L, Hall V, Brundin P (2008) Emerging restorative treatments for Parkinson's disease. Prog. Neurobiol. 85, 407-432.
87. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem. 283, 9089-9100.
88. Devor M (1999) Unexplained peculiarities of the dorsal root ganglion. Pain (Suppl 6), S27-S35.
89. Di Monte DA, Lavasani M, Manning-Bog AB (2002) Environmental factors in Parkinson's disease. Neurotoxicology 23, 487-502.
90. Dillin A, Kelly JW (2007) Medicine: the yin-yang of sirtuins. Science 317, 461-462.
91. Doorn KJ, Lucassen PJ, Boddeke HW, Prins M, Berendse HW, Drukarch B, van Dam AM (2012) Emerging roles of microglial activation and non-motor symptoms in Parkinson's disease. Prog. Neurobiol. 98, 222-238.
92. Doty RL (2012) Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8, 329-339.
93. Double KL, Dedov VN, Fedorow H, Kettle E, Halliday GM, Garner B, Brunk UT (2008) The comparative biology of neuromelanin and lipofuscin in the human brain. Cell. Mol. Life Sci. 65, 1669-1682.
94. Double KL, Reyes S, Werry EL, Halliday GM (2010) Selective cell death in neurodegeneration: why are some neurons spared in vulnerable regions? Prog. Neurobiol. 92, 316-329.
95. Driver JA, Logroscino G, Gaziano JM, Kurth T (2009) Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology 72, 432-438.
96. Duan W, Mattson MP (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. J. Neurosci. Res. 57, 195-206.
97. Edgar D, Trifunovic A (2009) The mtDNA mutator mouse: dissecting mitochondrial involvement in aging. Aging 1, 1028-1032.
98. Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, Holden JE, Kordower JH (1998) Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J. Comp. Neurol. 401, 253-265.
99. Ethell DW, Fei Q (2009) Parkinson-linked genes and toxins that affect neuronal cell death through the Bcl-2 family. Antioxid. Redox Signal. 11, 529-540.
100. Fan LW, Tien LT, Lin RC, Simpson KL, Rhodes PG, Cai Z (2011a) Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Neurobiol. Dis. 44, 304-316.
101. Fan LW, Tien LT, Zheng B, Pang Y, Lin RC, Simpson KL, Ma T, Rhodes PG, Cai Z (2011b) Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity. Brain Behav. Immun. 25, 286-297.
102. Faraonio R, Salerno P, Passaro F, Sedia C, Iaccio A, Bellelli R, Nappi TC, Comegna M, Romano S, Salvatore G, Santoro M, Cimino F (2012) A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts. Cell Death Differ. 19, 713-721.
103. Fayet G, Jansson M, Sternberg D, Moslemi AR, Blondy P, Lombes A, Fardeau M, Oldfors A (2002) Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function. Neuromuscul. Disord. 12, 484-493.
104. Fearnley JM, Lees AJ (1991) Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114(Pt 5), 2283-2301.
105. Fedorow H, Tribl F, Halliday G, Gerlach M, Riederer P, Double KL (2005) Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease. Prog. Neurobiol. 75, 109-124.
106. Ferrer I, Martinez A, Blanco R, Dalfo E, Carmona M (2011) Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease. J. Neural. Transm. 118, 821-839.
107. Fjell AM, Walhovd KB (2010) Structural brain changes in aging: courses, causes and cognitive consequences. Rev. Neurosci. 21, 187-221.
108. Flanary B (2005) The role of microglial cellular senescence in the aging and Alzheimer diseased brain. Rejuvenation Res. 8, 82-85.
109. Florenzano F (2012) Localization of axonal motor molecules machinery in neurodegenerative disorders. Int. J. Mol. Sci. 13, 5195-5206.
110. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92-105.
111. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J. Neurosci. 32, 7585-7593.
112. Galvan V, Jin K (2007) Neurogenesis in the aging brain. Clin. Interv. Aging 2, 605-610.
113. Galvin JE, Uryu K, Lee VM, Trojanowski JQ (1999) Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc. Natl Acad. Sci. USA 96, 13450-13455.
114. Gelinas DS, McLaurin J (2005) PPAR-alpha expression inversely correlates with inflammatory cytokines IL-1beta and TNF-alpha in aging rats. Neurochem. Res. 30, 1369-1375.
115. Gelmetti V, Ferraris A, Brusa L, Romano F, Lombardi F, Barzaghi C, Stanzione P, Garavaglia B, Dallapiccola B, Valente EM (2008) Late onset sporadic Parkinson's disease caused by PINK1 mutations: clinical and functional study. Mov. Disord. 23, 881-885.
116. Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM (2002) Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J. Neurochem. 80, 168-177.
117. Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO (1954) Oxygen poisoning and x-irradiation: a mechanism in common. Science 119, 623-626.
118. Gesi M, Soldani P, Giorgi FS, Santinami A, Bonaccorsi I, Fornai F (2000) The role of the locus coeruleus in the development of Parkinson's disease. Neurosci. Biobehav. Rev. 24, 655-668.
119. Giasson BI, Duda JE, Murray IV, Chen Q, Souza JM, Hurtig HI, Ischiropoulos H, Trojanowski JQ, Lee VM (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290, 985-989.
120. Gilley J, Seereeram A, Ando K, Mosely S, Andrews S, Kerschensteiner M, Misgeld T, Brion JP, Anderton B, Hanger DP, Coleman MP (2012) Age-dependent axonal transport and locomotor changes and tau hypophosphorylation in a "P301L" tau knockin mouse. Neurobiol. Aging 33, 621 e621-621 e615.
121. Godbout JP, Johnson RW (2004) Interleukin-6 in the aging brain. J. Neuroimmunol. 147, 141-144.
122. Going JJ, Stuart RC, Downie M, Fletcher-Monaghan AJ, Keith WN (2002) 'Senescence-associated' beta-galactosidase activity in the upper gastrointestinal tract. J. Pathol. 196, 394-400.
123. Gonzalez-Hernandez T, Barroso-Chinea P, Acevedo A, Salido E, Rodriguez M (2001) Colocalization of tyrosine hydroxylase and GAD65 mRNA in mesostriatal neurons. Eur. J. Neurosci. 13, 57-67.
124. Gonzalez-Hernandez T, Barroso-Chinea P, Rodriguez M (2004) Response of the GABAergic and dopaminergic mesostriatal projections to the lesion of the contralateral dopaminergic mesostriatal pathway in the rat. Mov. Disord. 19, 1029-1042.
125. Gonzalez-Perez O, Quinones-Hinojosa A (2012) Astrocytes as neural stem cells in the adult brain. J. Stem Cells 7, 181-188.
126. Gonzalez-Zulueta M, Ensz LM, Mukhina G, Lebovitz RM, Zwacka RM, Engelhardt JF, Oberley LW, Dawson VL, Dawson TM (1998) Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity. J. Neurosci. 18, 2040-2055.
127. Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346-1350.
128. Goss JR, Finch CE, Morgan DG (1991) Age-related changes in glial fibrillary acidic protein mRNA in the mouse brain. Neurobiol. Aging 12, 165-170.
129. Greenwood CE, Tatton WG, Seniuk NA, Biddle FG (1991) Increased dopamine synthesis in aging substantia nigra neurons. Neurobiol. Aging 12, 557-565.
130. Grote SS, Moses SG, Robins E, Hudgens RW, Croninger AB (1974) A study of selected catecholamine metabolizing enzymes: a comparison of depressive suicides and alcoholic suicides with controls. J. Neurochem. 23, 791-802.
131. Gu M, Cooper JM, Taanman JW, Schapira AH (1998) Mitochondrial DNA transmission of the mitochondrial defect in Parkinson's disease. Ann. Neurol. 44, 177-186.
132. Halliday GM (2009) Thalamic changes in Parkinson's disease. Parkinsonism Relat. Disord. 15(Suppl 3), S152-S155.
133. Halliday GM, Stevens CH (2011) Glia: initiators and progressors of pathology in Parkinson's disease. Mov. Disord. 26, 6-17.
134. Halliday GM, Fedorow H, Rickert CH, Gerlach M, Riederer P, Double KL (2006) Evidence for specific phases in the development of human neuromelanin. J. Neural. Transm. 113, 721-728.
135. Halliwell B (1992) Reactive oxygen species and the central nervous system. J. Neurochem. 59, 1609-1623.
136. Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA, Scott BL, Vance JM, Scott WK (2008) Pesticide exposure and risk of Parkinson's disease: a family-based case-control study. BMC Neurol. 8, 6.
137. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298-300.
138. Harman D (1972) The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145-147.
139. Harraz MM, Dawson TM, Dawson VL (2011) MicroRNAs in Parkinson's disease. J. Chem. Neuroanat. 42, 127-130.
140. Hayakawa N, Kato H, Araki T (2007) Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. Mech. Ageing Dev. 128, 311-316.
141. Haycock JW, Becker L, Ang L, Furukawa Y, Hornykiewicz O, Kish SJ (2003) Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J. Neurochem. 87, 574-585.
142. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67-93.
143. He YH, Lu X, Wu H, Cai WW, Yang LQ, Xu LY, Sun HP, Kong QP (2014) Mitochondrial DNA content contributes to healthy aging in Chinese: a study from nonagenarians and centenarians. Neurobiol. Aging 35, 1779 e1771-1779 e1774.
144. Henderson JM, Carpenter K, Cartwright H, Halliday GM (2000) Loss of thalamic intralaminar nuclei in progressive supranuclear palsy and Parkinson's disease: clinical and therapeutic implications. Brain 123(Pt 7), 1410-1421.
145. Herbener GH (1976) A morphometric study of age-dependent changes in mitochondrial population of mouse liver and heart. J. Gerontol. 31, 8-12.
146. Hess EJ, Bracha HS, Kleinman JE, Creese I (1987) Dopamine receptor subtype imbalance in schizophrenia. Life Sci. 40, 1487-1497.
147. Hipkiss AR (2014) Aging risk factors and Parkinson's disease: contrasting roles of common dietary constituents. Neurobiol. Aging 35, 1469-1472.
148. Hirai S (1968) [Histochemical study on the regressive degeneration of the senile brain, with special reference to the aging of the substantia nigra]. Shinkei Kenkyu No Shimpo 12, 845-849.
149. Hirrlinger J, Schulz JB, Dringen R (2002) Glutathione release from cultured brain cells: multidrug resistance protein 1 mediates the release of GSH from rat astroglial cells. J. Neurosci. Res. 69, 318-326.
150. Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc. Natl Acad. Sci. USA 84, 5976-5980.
151. Hirsch E, Graybiel AM, Agid YA (1988) Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334, 345-348.
152. Hirsch EC, Graybiel AM, Agid Y (1989) Selective vulnerability of pigmented dopaminergic neurons in Parkinson's disease. Acta Neurol. Scand. Suppl. 126, 19-22.
153. Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R (2007) How common are the "common" neurologic disorders? Neurology 68, 326-337.
154. Hjelmborg J vB, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K (2006) Genetic influence on human lifespan and longevity. Hum. Genet. 119, 312-321.
155. Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, Hirsch EC (2004) Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat. Neurosci. 7, 726-735.
156. Holliday R (1984) The biological significance of meiosis. Symp. Soc. Exp. Biol. 38, 381-394.
157. Hornykiewicz O (1989) Ageing and neurotoxins as causative factors in idiopathic Parkinson's disease-a critical analysis of the neurochemical evidence. Prog. Neuropsychopharmacol. Biol. Psychiatry 13, 319-328.
158. Hornykiewicz O (2008) Basic research on dopamine in Parkinson's disease and the discovery of the nigrostriatal dopamine pathway: the view of an eyewitness. Neurodegener. Dis. 5, 114-117.
159. Hornykiewicz O (2010) A brief history of levodopa. J. Neurol. 257, S249-S252.
160. Hubbard VM, Valdor R, Macian F, Cuervo AM (2012) Selective autophagy in the maintenance of cellular homeostasis in aging organisms. Biogerontology 13, 21-35.
161. Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, Hirsch EC (1996) Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72, 355-363.
162. Hwang O (2013) Role of oxidative stress in Parkinson's disease. Exp. Neurobiol. 22, 11-17.
163. Ibanez P, De Michele G, Bonifati V, Lohmann E, Thobois S, Pollak P, Agid Y, Heutink P, Durr A, Brice A (2003) Screening for DJ-1 mutations in early onset autosomal recessive parkinsonism. Neurology 61, 1429-1431.
164. Irrcher I, Aleyasin H, Seifert EL, Hewitt SJ, Chhabra S, Phillips M, Lutz AK, Rousseaux MW, Bevilacqua L, Jahani-Asl A, Callaghan S, MacLaurin JG, Winklhofer KF, Rizzu P, Rippstein P, Kim RH, Chen CX, Fon EA, Slack RS, Harper ME, McBride HM, Mak TW, Park DS (2010) Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum. Mol. Genet. 19, 3734-3746.
165. Ishibashi K, Oda K, Ishiwata K, Ishii K (2014) Comparison of dopamine transporter decline in a patient with Parkinson's disease and normal aging effect. J. Neurol. Sci. 339, 207-209.
166. Isobe K, Cheng Z, Nishio N, Suganya T, Tanaka Y, Ito S (2014) iPSCs, aging and age-related diseases. N. Biotechnol. 31, 411-421.
167. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res. Mol. Brain Res. 57, 1-9.
168. Iversen LL, Rossor MN, Reynolds GP, Hills R, Roth M, Mountjoy CQ, Foote SL, Morrison JH, Bloom FE (1983) Loss of pigmented dopamine-beta-hydroxylase positive cells from locus coeruleus in senile dementia of Alzheimer's type. Neurosci. Lett. 39, 95-100.
169. Jadiya P, Chatterjee M, Sammi SR, Kaur S, Palit G, Nazir A (2011) Sir-2.1 modulates 'calorie-restriction-mediated' prevention of neurodegeneration in Caenorhabditis elegans: implications for Parkinson's disease. Biochem. Biophys. Res. Commun. 413, 306-310.
170. Jang YC, Van Remmen H (2009) The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp. Gerontol. 44, 256-260.
171. Jellinger KA (2002) Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts. Mov. Disord. 27, 8-30.
172. Jenner P (2003) Oxidative stress in Parkinson's disease. Ann. Neurol. 53(Suppl 3), S26-S36; discussion S36-28.
173. Jenner P (2007) Oxidative stress and Parkinson's disease. Handb. Clin. Neurol. 83, 507-520.
174. Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech. Ageing Dev. 129, 467-474.
175. Jin F, Wu Q, Lu YF, Gong QH, Shi JS (2008) Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats. Eur. J. Pharmacol. 600, 78-82.
176. Junn E, Mouradian MM (2012) MicroRNAs in neurodegenerative diseases and their therapeutic potential. Pharmacol. Ther. 133, 142-150.
177. Kanaan NM, Kordower JH, Collier TJ (2007) Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability. J. Comp. Neurol. 502, 683-700.
178. Kanaan NM, Kordower JH, Collier TJ (2008) Age-related changes in dopamine transporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons: relevance in selective neuronal vulnerability to degeneration. Eur. J. Neurosci. 27, 3205-3215.
179. Kastner A, Hirsch EC, Herrero MT, Javoy-Agid F, Agid Y (1993) Immunocytochemical quantification of tyrosine hydroxylase at a cellular level in the mesencephalon of control subjects and patients with Parkinson's and Alzheimer's disease. J. Neurochem. 61, 1024-1034.
180. Kayali R, Aydin S, Cakatay U (2009) Effect of gender on main clinical chemistry parameters in aged rats. Curr. Aging Sci. 2, 67-71.
181. Kidd PM (2000) Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management. Altern. Med. Rev. 5, 502-529.
182. Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A (2007) A MicroRNA feedback circuit in midbrain dopamine neurons. Science 317, 1220-1224.
183. Kish SJ, Shannak K, Hornykiewicz O (1988) Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. N. Engl. J. Med. 318, 876-880.
184. Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O (1992) Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson's disease. J. Neurochem. 58, 642-648.
185. Knott C, Stern G, Wilkin GP (2000) Inflammatory regulators in Parkinson's disease: iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Mol. Cell Neurosci. 16, 724-739.
186. Kohama SG, Goss JR, Finch CE, McNeill TH (1995) Increases of glial fibrillary acidic protein in the aging female mouse brain. Neurobiol. Aging 16, 59-67.
187. Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, Halliday GM, Bartus RT (2013) Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 136, 2419-2431.
188. Kraytsberg Y, Kudryavtseva E, McKee AC, Geula C, Kowall NW, Khrapko K (2006) Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518-520.
189. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312-318.
190. Kusnoor SV, Muly EC, Morgan JI, Deutch AY (2009) Is the loss of thalamostriatal neurons protective in parkinsonism? Parkinsonism Relat. Disord. 15(Suppl 3), S162-S166.
191. Lambert AJ, Boysen HM, Buckingham JA, Yang T, Podlutsky A, Austad SN, Kunz TH, Buffenstein R, Brand MD (2007) Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms. Aging Cell 6, 607-618.
192. Langston JW, Ballard P (1984) Parkinsonism induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP): implications for treatment and the pathogenesis of Parkinson's disease. Can. J. Neurol. Sci. 11, 160-165.
193. Lansbury PT Jr, Brice A (2002) Genetics of Parkinson's disease and biochemical studies of implicated gene products. Curr. Opin. Genet. Dev. 12, 299-306.
194. de Lau LM, Bornebroek M, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM (2005) Dietary fatty acids and the risk of Parkinson disease: the Rotterdam study. Neurology 64, 2040-2045.
195. Lauri A, Pompilio G, Capogrossi MC (2014) The mitochondrial genome in aging and senescence. Ageing Res. Rev. 18, 1-15.
196. Lauri A, Pompilio G, Capogrossi MC (2014b) The mitochondrial genome in aging and senescence. Ageing Res. Rev. 18C, 1-15.
197. Lee T, Seeman P, Rajput A, Farley IJ, Hornykiewicz O (1978) Receptor basis for dopaminergic supersensitivity in Parkinson's disease. Nature 273, 59-61.
198. Lee HJ, Suk JE, Patrick C, Bae EJ, Cho JH, Rho S, Hwang D, Masliah E, Lee SJ (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synucleinopathies. J. Biol. Chem. 285, 9262-9272.
199. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH (1998) The ubiquitin pathway in Parkinson's disease. Nature 395, 451-452.
200. Levy G (2007) The relationship of Parkinson disease with aging. Arch. Neurol. 64, 1242-1246.
201. Li W, Lesuisse C, Xu Y, Troncoso JC, Price DL, Lee MK (2004) Stabilization of alpha-synuclein protein with aging and familial Parkinson's disease-linked A53T mutation. J. Neurosci. 24, 7400-7409.
202. Li N, Bates DJ, An J, Terry DA, Wang E (2011) Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol. Aging 32, 944-955.
203. Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130-1132.
204. Ling Z, Gayle DA, Ma SY, Lipton JW, Tong CW, Hong JS, Carvey PM (2002) In utero bacterial endotoxin exposure causes loss of tyrosine hydroxylase neurons in the postnatal rat midbrain. Mov. Disord. 17, 116-124.
205. Linnane AW, Marzuki S, Ozawa T, Tanaka M (1989) Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642-645.
206. Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D Jr, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E (2007a) The etiopathogenesis of Parkinson disease and suggestions for future research. Part II. J. Neuropathol. Exp. Neurol. 66, 329-336.
207. Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D Jr, Price DL (2007b) The etiopathogenesis of Parkinson disease and suggestions for future research. Part I. J. Neuropathol. Exp. Neurol. 66, 251-257.
208. Liu JP (2014) Molecular mechanisms of aging and related diseases. Clin. Exp. Pharmacol. Physiol. 41, 445-458.
209. Liu XH, Kato H, Araki T, Itoyama Y, Kato K, Kogure K (1994) An immunohistochemical observation of manganese superoxide dismutase in rat substantia nigra after occlusion of middle cerebral artery. Neurosci. Lett. 173, 103-106.
210. Liu J, Wang YY, Liu L, Wang QD, Yuan ZY, Zhang ZX, Gu P, Wang MW (2008) Damage to the nigrostriatal system in the MPTP-treated SAMP8 mouse. Neurosci. Lett. 448, 184-188.
211. Liu K, Shi N, Sun Y, Zhang T, Sun X (2013) Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice. Neurochem. Res. 38, 201-207.
212. Lloyd K, Hornykiewicz O (1970) Parkinson's disease: activity of L-dopa decarboxylase in discrete brain regions. Science 170, 1212-1213.
213. Lohr JB, Jeste DV (1988) Locus ceruleus morphometry in aging and schizophrenia. Acta Psychiatr. Scand. 77, 689-697.
214. Longo VD, Mitteldorf J, Skulachev VP (2005) Programmed and altruistic ageing. Nat. Rev. Genet. 6, 866-872.
215. Lucking CB, Abbas N, Durr A, Bonifati V, Bonnet AM, de Broucker T, De Michele G, Wood NW, Agid Y, Brice A (1998) Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet 352, 1355-1356.
216. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A (2000) Association between early-onset Parkinson's disease and mutations in the parkin gene. N. Engl. J. Med. 342, 1560-1567.
217. Lynch AM, Murphy KJ, Deighan BF, O'Reilly JA, Gun'ko YK, Cowley TR, Gonzalez-Reyes RE, Lynch MA (2010) The impact of glial activation in the aging brain. Aging Dis. 1, 262-278.
218. Ma SY, Roytt M, Collan Y, Rinne JO (1999) Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol. Appl. Neurobiol. 25, 394-399.
219. Mack AF, Wolburg H (2013) A novel look at astrocytes: aquaporins, ionic homeostasis, and the role of the microenvironment for regeneration in the CNS. Neuroscientist 19, 195-207.
220. de Magalhaes JP, Costa J (2009) A database of vertebrate longevity records and their relation to other life-history traits. J. Evol. Biol. 22, 1770-1774.
221. de Magalhaes JP, Wuttke D, Wood SH, Plank M, Vora C (2012) Genome-environment interactions that modulate aging: powerful targets for drug discovery. Pharmacol. Rev. 64, 88-101.
222. Magenta A, Greco S, Gaetano C, Martelli F (2013) Oxidative stress and microRNAs in vascular diseases. Int. J. Mol. Sci. 14, 17319-17346.
223. Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166-1175.
224. Manaye KF, McIntire DD, Mann DM, German DC (1995) Locus coeruleus cell loss in the aging human brain: a non-random process. J. Comp. Neurol. 358, 79-87.
225. Mann DM (1983) The locus coeruleus and its possible role in ageing and degenerative disease of the human central nervous system. Mech. Ageing Dev. 23, 73-94.
226. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J. Biol. Chem. 277, 1641-1644.
227. Mansour H, Chamberlain CG, Weible MW II, Hughes S, Chu Y, Chan-Ling T (2008) Aging-related changes in astrocytes in the rat retina: imbalance between cell proliferation and cell death reduces astrocyte availability. Aging Cell 7, 526-540.
228. Marinova-Mutafchieva L, Sadeghian M, Broom L, Davis JB, Medhurst AD, Dexter DT (2009) Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6-hydroxydopamine model of Parkinson's disease. J. Neurochem. 110, 966-975.
229. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey AC, Mazzulli J, Mosharov EV, Hodara R, Fredenburg R, Wu DC, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury PT, Sulzer D, Cuervo AM (2008) Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777-788.
230. Maruszak A, Gaweda-Walerych K, Soltyszewski I, Zekanowski C (2006) Mitochondrial DNA in pathogenesis of Alzheimer's and Parkinson's diseases. Acta Neurobiol. Exp. 66, 153-176.
231. Marzban G, Grillari J, Reisinger E, Hemetsberger T, Grabherr R, Katinger H (2002) Age-related alterations in the protein expression profile of C57BL/6J mouse pituitaries. Exp. Gerontol. 37, 1451-1460.
232. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444-453.
233. Mattson MP, Maudsley S, Martin B (2004) A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res. Rev. 3, 445-464.
234. McCormack AL, Di Monte DA, Delfani K, Irwin I, DeLanney LE, Langston WJ, Janson AM (2004) Aging of the nigrostriatal system in the squirrel monkey. J. Comp. Neurol. 471, 387-395.
235. McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch. Neurol. 34, 33-35.
236. McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann. Neurol. 24, 574-576.
237. Medvedev ZA (1981) On the immortality of the germ line: genetic and biochemical mechanism. A review. Mech. Ageing Dev. 17, 331-359.
238. Meulener MC, Xu K, Thomson L, Ischiropoulos H, Bonini NM (2006) Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc. Natl Acad. Sci. USA 103, 12517-12522.
239. Miller RA (1999) Kleemeier award lecture: are there genes for aging? J. Gerontol. A Biol. Sci. Med. Sci. 54, B297-B307.
240. Miller J, Sanders E, Webb D (1978) Plasmapheresis for paraquat poisoning. Lancet 1, 875-876.
241. Miller GW, Erickson JD, Perez JT, Penland SN, Mash DC, Rye DB, Levey AI (1999) Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson's disease. Exp. Neurol. 156, 138-148.
242. Miquel J, Economos AC, Fleming J, Johnson JE Jr (1980) Mitochondrial role in cell aging. Exp. Gerontol. 15, 575-591.
243. Mirza B, Hadberg H, Thomsen P, Moos T (2000) The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience 95, 425-432.
244. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075.
245. Moore DJ, West AB, Dawson VL, Dawson TM (2005) Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57-87.
246. Mor F, Quintana F, Mimran A, Cohen IR (2003) Autoimmune encephalomyelitis and uveitis induced by T cell immunity to self beta-synuclein. J. Immunol. 170, 628-634.
247. Morales I, Rodriguez M (2012) Self-induced accumulation of glutamate in striatal astrocytes and basal ganglia excitotoxicity. Glia 60, 1481-1494.
248. Morales I, Sabate M, Rodriguez M (2013a) Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease. Eur. J. Neurosci. 38, 2172-2182.
249. Morales I, Yanos C, Rodriguez-Sabate C, Sanchez A, Rodriguez M (2013b) Striatal glutamate degenerates thalamic neurons. J. Neuropathol. Exp. Neurol. 72, 286-297.
250. Morfini G, Pigino G, Opalach K, Serulle Y, Moreira JE, Sugimori M, Llinas RR, Brady ST (2007) 1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C. Proc. Natl Acad. Sci. USA 104, 2442-2447.
251. Morgan DG, Marcusson JO, Nyberg P, Wester P, Winblad B, Gordon MN, Finch CE (1987) Divergent changes in D-1 and D-2 dopamine binding sites in human brain during aging. Neurobiol. Aging 8, 195-201.
252. Mortera P, Herculano-Houzel S (2012) Age-related neuronal loss in the rat brain starts at the end of adolescence. Front. Neuroanat. 6, 45.
253. Mount MP, Lira A, Grimes D, Smith PD, Faucher S, Slack R, Anisman H, Hayley S, Park DS (2007) Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. J. Neurosci. 27, 3328-3337.
254. Mouradian MM (2012) MicroRNAs in Parkinson's disease. Neurobiol. Dis. 46, 279-284.
255. Mozley PD, Acton PD, Barraclough ED, Plossl K, Gur RC, Alavi A, Mathur A, Saffer J, Kung HF (1999) Effects of age on dopamine transporters in healthy humans. J. Nucl. Med. 40, 1812-1817.
256. Muftuoglu M, Elibol B, Dalmizrak O, Ercan A, Kulaksiz G, Ogus H, Dalkara T, Ozer N (2004) Mitochondrial complex I and IV activities in leukocytes from patients with parkin mutations. Mov. Disord. 19, 544-548.
257. Muller CM, de Vos RA, Maurage CA, Thal DR, Tolnay M, Braak H (2005) Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability. J. Neuropathol. Exp. Neurol. 64, 623-628.
258. Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007) Trends in oxidative aging theories. Free Radic. Biol. Med. 43, 477-503.
259. Muller-Hocker J (1989) Cytochrome-c-oxidase deficient cardiomyocytes in the human heart-an age-related phenomenon. A histochemical ultracytochemical study. Am. J. Pathol. 134, 1167-1173.
260. Muller-Hocker J (1990) Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J. Neurol. Sci. 100, 14-21.
261. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem. J. 417, 1-13.
262. Nagelhus EA, Amiry-Moghaddam M, Bergersen LH, Bjaalie JG, Eriksson J, Gundersen V, Leergaard TB, Morth JP, Storm-Mathisen J, Torp R, Walhovd KB, Tonjum T (2013) The glia doctrine: addressing the role of glial cells in healthy brain ageing. Mech. Ageing Dev. 134, 449-459.
263. Nakabeppu Y, Tsuchimoto D, Yamaguchi H, Sakumi K (2007) Oxidative damage in nucleic acids and Parkinson's disease. J. Neurosci. Res. 85, 919-934.
264. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA, Shen J, Cookson MR, Youle RJ (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298.
265. Neukomm LJ, Freeman MR (2014) Diverse cellular and molecular modes of axon degeneration. Trends Cell Biol. 24, 515-523.
266. Nguyen D, Alavi MV, Kim KY, Kang T, Scott RT, Noh YH, Lindsey JD, Wissinger B, Ellisman MH, Weinreb RN, Perkins GA, Ju WK (2011) A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics. Cell Death Dis. 2, e240.
267. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318.
268. Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ (2012) Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol. Aging 33, 195e1-195e12.
269. Numao A, Suzuki K, Miyamoto M, Miyamoto T, Hirata K (2014) Clinical correlates of serum insulin-like growth factor-1 in patients with Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. Parkinsonism Relat. Disord. 20, 212-216.
270. Nunomura A, Moreira PI, Lee HG, Zhu X, Castellani RJ, Smith MA, Perry G (2007) Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS Neurol. Disord. Drug Targets 6, 411-423.
271. Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G (2010) Missing pieces in the Parkinson's disease puzzle. Nat. Med. 16, 653-661.
272. Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem. Pharmacol. 73, 550-560.
273. Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson's disease. Annu. Rev. Neurosci. 22, 123-144.
274. Oliveira BF, Nogueira-Machado JA, Chaves MM (2010) The role of oxidative stress in the aging process. ScientificWorldJournal 10, 1121-1128.
275. Olivieri F, Lazzarini R, Recchioni R, Marcheselli F, Rippo MR, Di Nuzzo S, Albertini MC, Graciotti L, Babini L, Mariotti S, Spada G, Abbatecola AM, Antonicelli R, Franceschi C, Procopio AD (2012) MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling. Age 35, 1157-1172.
276. Olson CB (1987) A review of why and how we age: a defense of multifactorial aging. Mech. Ageing Dev. 41, 1-28.
277. Orimo S, Uchihara T, Kanazawa T, Itoh Y, Wakabayashi K, Kakita A, Takahashi H (2011) Unmyelinated axons are more vulnerable to degeneration than myelinated axons of the cardiac nerve in Parkinson's disease. Neuropathol. Appl. Neurobiol. 37, 791-802.
278. Orr CF, Rowe DB, Mizuno Y, Mori H, Halliday GM (2005) A possible role for humoral immunity in the pathogenesis of Parkinson's disease. Brain 128, 2665-2674.
279. Orth M, Schapira AH (2002) Mitochondrial involvement in Parkinson's disease. Neurochem. Int. 40, 533-541.
280. Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, Sato Y, Nishikawa K, Sun YJ, Sakurai M, Harada T, Hara Y, Kimura I, Chiba S, Namikawa K, Kiyama H, Noda M, Aoki S, Wada K (2003) Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum. Mol. Genet. 12, 1945-1958.
281. Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T (2005) Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann. Neurol. 57, 168-175.
282. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516-519.
283. Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, Wacker M, Klose J, Shen J (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614-18622.
284. Palikaras K, Tavernarakis N (2012) Mitophagy in neurodegeneration and aging. Front. Genet. 3, 297.
285. Pallas M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, Yeste-Velasco M, Folch J, Canudas AM, Sureda FX, Ferrer I, Camins A (2008) Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neuroscience 154, 1388-1397.
286. Paolini M, Sapone A, Gonzalez FJ (2004) Parkinson's disease, pesticides and individual vulnerability. Trends Pharmacol. Sci. 25, 124-129.
287. Parker WD Jr, Boyson SJ, Parks JK (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann. Neurol. 26, 719-723.
288. Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S (2014) Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice. Neuroscience 277, 747-754.
289. Paulus W, Jellinger K (1991) The neuropathologic basis of different clinical subgroups of Parkinson's disease. J. Neuropathol. Exp. Neurol. 50, 743-755.
290. Pearce RK, Owen A, Daniel S, Jenner P, Marsden CD (1997) Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease. J. Neural. Transm. 104, 661-677.
291. Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc. Natl Acad. Sci. USA 106, 3059-3064.
292. Pertusa M, Garcia-Matas S, Rodriguez-Farre E, Sanfeliu C, Cristofol R (2007) Astrocytes aged in vitro show a decreased neuroprotective capacity. J. Neurochem. 101, 794-805.
293. Peto R, Doll R (1997) There is no such thing as aging. BMJ 315, 1030-1032.
294. Pfeiffer RF (2003) Gastrointestinal dysfunction in Parkinson's disease. Lancet Neurol. 2, 107-116.
295. Pfeiffer RF (2010) Gastrointestinal, urological, and sexual dysfunction in Parkinson's disease. Mov. Disord. 25(Suppl 1), S94-S97.
296. Pirker W, Asenbaum S, Hauk M, Kandlhofer S, Tauscher J, Willeit M, Neumeister A, Praschak-Rieder N, Angelberger P, Brucke T (2000) Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging. J. Nucl. Med. 41, 36-44.
297. Prinzinger R (2005) Programmed ageing: the theory of maximal metabolic scope. How does the biological clock tick? EMBO Rep. 6 Spec No, S14-S19.
298. Pucciarelli S, Moreschini B, Micozzi D, De Fronzo GS, Carpi FM, Polzonetti V, Vincenzetti S, Mignini F, Napolioni V (2012) Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res. 15, 590-595.
299. Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res. Brain Res. Rev. 30, 77-105.
300. Ramsay RR, Krueger MJ, Youngster SK, Gluck MR, Casida JE, Singer TP (1991) Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase. J. Neurochem. 56, 1184-1190.
301. Ransmayr G, Faucheux B, Nowakowski C, Kubis N, Federspiel S, Kaufmann W, Henin D, Hauw JJ, Agid Y, Hirsch EC (2000) Age-related changes of neuronal counts in the human pedunculopontine nucleus. Neurosci. Lett. 288, 195-198.
302. Raule N, Sevini F, Li S, Barbieri A, Tallaro F, Lomartire L, Vianello D, Montesanto A, Moilanen JS, Bezrukov V, Blanche H, Hervonen A, Christensen K, Deiana L, Gonos ES, Kirkwood TB, Kristensen P, Leon A, Pelicci PG, Poulain M, Rea IM, Remacle J, Robine JM, Schreiber S, Sikora E, Eline Slagboom P, Spazzafumo L, Antonietta Stazi M, Toussaint O, Vaupel JW, Rose G, Majamaa K, Perola M, Johnson TE, Bolund L, Yang H, Passarino G, Franceschi C (2013) The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. Aging Cell 13, 401-407.
303. Reddy PH, Beal MF (2005) Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res. Brain Res. Rev. 49, 618-632.
304. Reeve A, Meagher M, Lax N, Simcox E, Hepplewhite P, Jaros E, Turnbull D (2013) The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons. J. Neurosci. 33, 10790-10801.
305. Reeve A, Simcox E, Turnbull D (2014) Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 14, 19-30.
306. Rice ME, Russo-Menna I (1998) Differential compartmentalization of brain ascorbate and glutathione between neurons and glia. Neuroscience 82, 1213-1223.
307. Richter C (1992) Reactive oxygen and DNA damage in mitochondria. Mutat. Res. 275, 249-255.
308. Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson's disease. A detailed study of influential factors in human brain amine analysis. J. Neural. Transm. 38, 277-301.
309. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MB (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52, 515-520.
310. Robinson DS, Sourkes TL, Nies A, Harris LS, Spector S, Bartlett DL, Kaye IS (1977) Monoamine metabolism in human brain. Arch. Gen. Psychiatry 34, 89-92.
311. Rodriguez M, Castro R (1991) Apomorphine lowers dopamine synthesis for up to 48 h: implications for drug sensitization. NeuroReport 2, 365-368.
312. Rodriguez Diaz M, Abdala P, Barroso-Chinea P, Obeso J, Gonzalez-Hernandez T (2001) Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson's disease. Behav. Brain Res. 122, 79-92.
313. Rodriguez M, Gonzalez-Hernandez T (1999) Electrophysiological and morphological evidence for a GABAergic nigrostriatal pathway. J. Neurosci. 19, 4682-4694.
314. Rodriguez M, Barroso-Chinea P, Abdala P, Obeso J, Gonzalez-Hernandez T (2001) Dopamine cell degeneration induced by intraventricular administration of 6-hydroxydopamine in the rat: similarities with cell loss in Parkinson's disease. Exp. Neurol. 169, 163-181.
315. Rodriguez M, Sabate M, Rodriguez-Sabate C, Morales I (2012) The role of non-synaptic extracellular glutamate. Brain Res. Bull. 93, 17-26.
316. Rodriguez-Navarro JA, Casarejos MJ, Menendez J, Solano RM, Rodal I, Gomez A, Yebenes JG, Mena MA (2007) Mortality, oxidative stress and tau accumulation during ageing in parkin null mice. J. Neurochem. 103, 98-114.
317. Rogers J, Mastroeni D, Leonard B, Joyce J, Grover A (2007) Neuroinflammation in Alzheimer's disease and Parkinson's disease: are microglia pathogenic in either disorder? Int. Rev. Neurobiol. 82, 235-246.
318. Rudow G, O'Brien R, Savonenko AV, Resnick SM, Zonderman AB, Pletnikova O, Marsh L, Dawson TM, Crain BJ, West MJ, Troncoso JC (2008) Morphometry of the human substantia nigra in ageing and Parkinson's disease. Acta Neuropathol. 115, 461-470.
319. Saavedra A, Baltazar G, Santos P, Carvalho CM, Duarte EP (2006) Selective injury to dopaminergic neurons up-regulates GDNF in substantia nigra postnatal cell cultures: role of neuron-glia crosstalk. Neurobiol. Dis. 23, 533-542.
320. Sanchez-Danes A, Richaud-Patin Y, Carballo-Carbajal I, Jimenez-Delgado S, Caig C, Mora S, Di Guglielmo C, Ezquerra M, Patel B, Giralt A, Canals JM, Memo M, Alberch J, Lopez-Barneo J, Vila M, Cuervo AM, Tolosa E, Consiglio A, Raya A (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. EMBO Mol. Med. 4, 380-395.
321. Sasaki S, Warita H, Abe K, Iwata M (2005) Impairment of axonal transport in the axon hillock and the initial segment of anterior horn neurons in transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol. 110, 48-56.
322. Saura J, Andres N, Andrade C, Ojuel J, Eriksson K, Mahy N (1997) Biphasic and region-specific MAO-B response to aging in normal human brain. Neurobiol. Aging 18, 497-507.
323. Seidler A, Hellenbrand W, Robra BP, Vieregge P, Nischan P, Joerg J, Oertel WH, Ulm G, Schneider E (1996) Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany. Neurology 46, 1275-1284.
324. Sellbach AN, Boyle RS, Silburn PA, Mellick GD (2006) Parkinson's disease and family history. Parkinsonism Relat. Disord. 12, 399-409.
325. Semchuk KM, Love EJ, Lee RG (1992) Parkinson's disease and exposure to agricultural work and pesticide chemicals. Neurology 42, 1328-1335.
326. Sethi P, Lukiw WJ (2009) Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex. Neurosci. Lett. 459, 100-104.
327. Shapira E, Ratzon R, Shoham-Vardi I, Serjienko R, Mazor M, Bashiri A (2002) Primary vs. secondary recurrent pregnancy loss-epidemiological characteristics, etiology, and next pregnancy outcome. J. Perinat. Med. 40, 389-396.
328. Shibata E, Sasaki M, Tohyama K, Kanbara Y, Otsuka K, Ehara S, Sakai A (2006) Age-related changes in locus ceruleus on neuromelanin magnetic resonance imaging at 3 Tesla. Magn. Reson. Med. Sci. 5, 197-200.
329. Shimada A, Hasegawa-Ishii S (2011) Senescence-accelerated Mice (SAMs) as a Model for Brain Aging and Immunosenescence. Aging Dis. 2, 414-435.
330. Shook BA, Manz DH, Peters JJ, Kang S, Conover JC (2012) Spatiotemporal changes to the subventricular zone stem cell pool through aging. J. Neurosci. 32, 6947-6956.
331. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson's disease and other neurodegenerative disorders affecting basal ganglia. Ann. Neurol. 36, 348-355.
332. Sinclair DA, Oberdoerffer P (2009) The ageing epigenome: damaged beyond repair? Ageing Res. Rev. 8, 189-198.
333. Smigrodzki RM, Khan SM (2005) Mitochondrial microheteroplasmy and a theory of aging and age-related disease. Rejuvenation Res. 8, 172-198.
334. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol. 119, 7-35.
335. Sohal RS, Brunk UT (1992) Mitochondrial production of pro-oxidants and cellular senescence. Mutat. Res. 275, 295-304.
336. Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic. Biol. Med. 52, 539-555.
337. Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273, 59-63.
338. Song YJ, Halliday GM, Holton JL, Lashley T, O'Sullivan SS, McCann H, Lees AJ, Ozawa T, Williams DR, Lockhart PJ, Revesz TR (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J. Neuropathol. Exp. Neurol. 68, 1073-1083.
339. Sossi V, de La Fuente-Fernandez R, Holden JE, Doudet DJ, McKenzie J, Stoessl AJ, Ruth TJ (2002) Increase in dopamine turnover occurs early in Parkinson's disease: evidence from a new modeling approach to PET 18F-fluorodopa data. J. Cereb. Blood Flow Metab. 22, 232-239.
340. Srivastava S, Haigis MC (2011) Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer's and Parkinson's diseases. Curr. Pharm. Des. 17, 3418-3433.
341. Stark AK, Pakkenberg B (2004) Histological changes of the dopaminergic nigrostriatal system in aging. Cell Tissue Res. 318, 81-92.
342. Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J. Neurosci. 21, 9549-9560.
343. Sterky FH, Lee S, Wibom R, Olson L, Larsson NG (2011) Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo. Proc. Natl Acad. Sci. USA 108, 12937-12942.
344. Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40, 133-139.
345. Streit WJ, Graeber MB, Kreutzberg GW (1989) Expression of Ia antigen on perivascular and microglial cells after sublethal and lethal motor neuron injury. Exp. Neurol. 105, 115-126.
346. Streit WJ, Miller KR, Lopes KO, Njie E (2008) Microglial degeneration in the aging brain-bad news for neurons? Front Biosci. 13, 3423-3438.
347. Subramaniam SR, Chesselet MF (2013) Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Prog. Neurobiol. 106-107, 17-32.
348. Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T, Tateno Y (1991) Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacology 103, 41-45.
349. Swerdlow RH, Parks JK, Miller SW, Tuttle JB, Trimmer PA, Sheehan JP, Bennett JP Jr, Davis RE, Parker WD Jr (1996) Origin and functional consequences of the complex I defect in Parkinson's disease. Ann. Neurol. 40, 663-671.
350. Tacutu R, Craig T, Budovsky A, Wuttke D, Lehmann G, Taranukha D, Costa J, Fraifeld VE, de Magalhaes JP (2012) Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res. 41, D1027-D1033.
351. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.
352. Takeda T (2009) Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice. Neurochem. Res. 34, 639-659.
353. Takubo K, Izumiyama-Shimomura N, Honma N, Sawabe M, Arai T, Kato M, Oshimura M, Nakamura K (2002) Telomere lengths are characteristic in each human individual. Exp. Gerontol. 37, 523-531.
354. Tanner CM (1989) The role of environmental toxins in the etiology of Parkinson's disease. Trends Neurosci. 12, 49-54.
355. Tate EL, Herbener GH (1976) A morphometric study of the density of mitochondrial cristae in heart and liver of aging mice. J. Gerontol. 31, 129-134.
356. Tedroff J, Aquilonius SM, Hartvig P, Lundqvist H, Gee AG, Uhlin J, Langstrom B (1988) Monoamine re-uptake sites in the human brain evaluated in vivo by means of 11C-nomifensine and positron emission tomography: the effects of age and Parkinson's disease. Acta Neurol. Scand. 77, 192-201.
357. Toussaint O, Dumont P, Dierick JF, Pascal T, Frippiat C, Chainiaux F, Sluse F, Eliaers F, Remacle J (2000) Stress-induced premature senescence. Essence of life, evolution, stress, and aging. Ann. N. Y. Acad. Sci. 908, 85-98.
358. Ungerstedt U (1971) Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. Suppl. 367, 95-122.
359. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004a) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160.
360. Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR (2004b) PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann. Neurol. 56, 336-341.
361. Van Humbeeck C, Cornelissen T, Hofkens H, Mandemakers W, Gevaert K, De Strooper B, Vandenberghe W (2011) Parkin interacts with Ambra1 to induce mitophagy. J. Neurosci. 31, 10249-10261.
362. Vanitallie TB, Nonas C, Di Rocco A, Boyar K, Hyams K, Heymsfield SB (2005) Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology 64, 728-730.
363. Venkateshappa C, Harish G, Mythri RB, Mahadevan A, Bharath MM, Shankar SK (2012) Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease. Neurochem. Res. 37, 358-369.
364. Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39, 540-543.
365. Vincow ES, Merrihew G, Thomas RE, Shulman NJ, Beyer RP, MacCoss MJ, Pallanck LJ (2013) The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl Acad. Sci. USA 110, 6400-6405.
366. Volkow ND, Fowler JS, Gatley SJ, Logan J, Wang GJ, Ding YS, Dewey S (1996) PET evaluation of the dopamine system of the human brain. J. Nucl. Med. 37, 1242-1256.
367. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol. 99, 14-20.
368. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974-3980.
369. Wang D, Kreutzer DA, Essigmann JM (1998a) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat. Res. 400, 99-115.
370. Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, Huser JM, Snow BJ, Ruth TJ, Calne DB, Stoessl AJ (1998b) Age-dependent decline of dopamine D1 receptors in human brain: a PET study. Synapse 30, 56-61.
371. Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009) PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons. J. Biol. Chem. 284, 21379-21385.
372. Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009-25013.
373. Weihofen A, Thomas KJ, Ostaszewski BL, Cookson MR, Selkoe DJ (2009) Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking. Biochemistry 48, 2045-2052.
374. Weisskopf MG, Knekt P, O'Reilly EJ, Lyytinen J, Reunanen A, Laden F, Altshul L, Ascherio A (2010) Persistent organochlorine pesticides in serum and risk of Parkinson disease. Neurology 74, 1055-1061.
375. Werner CJ, Heyny-von Haussen R, Mall G, Wolf S (2008) Proteome analysis of human substantia nigra in Parkinson's disease. Proteome Sci. 6, 8.
376. Wilson PD, Franks LM (1975) The effect of age on mitochondrial ultrastructure. Gerontologia 21, 81-94.
377. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J (2011) Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur. J. Epidemiol. 26(Suppl 1), S1-S58.
378. Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat. Neurosci. 13, 805-811.
379. Wood-Kaczmar A, Gandhi S, Yao Z, Abramov AY, Miljan EA, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen MR, Latchman D, Tabrizi SJ, Wood NW (2008) PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE 3, e2455.
380. Yang ML, Hasadsri L, Woods WS, George JM (2010) Dynamic transport and localization of alpha-synuclein in primary hippocampal neurons. Mol. Neurodegener. 5, 9.
381. Yen WL, Klionsky DJ (2008) How to live long and prosper: autophagy, mitochondria, and aging. Physiology 23, 248-262.
382. Yu BP (1996) Aging and oxidative stress: modulation by dietary restriction. Free Radic. Biol. Med. 21, 651-668.
383. Yu BP, Yang R (1996) Critical evaluation of the free radical theory of aging. A proposal for the oxidative stress hypothesi. Ann. N. Y. Acad. Sci. 786, 1-11.
384. Zeevalk GD, Razmpour R, Bernard LP (2008) Glutathione and Parkinson's disease: is this the elephant in the room? Biomed. Pharmacother. 62, 236-249.
385. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, Wilson B, Zhang W, Zhou Y, Hong JS, Zhang J (2005) Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. Faseb J. 19, 533-542.
386. Zhang F, Wang S, Gan L, Vosler PS, Gao Y, Zigmond MJ, Chen J (2011) Protective effects and mechanisms of sirtuins in the nervous system. Prog. Neurobiol. 95, 373-395.
387. Zhao T, Li J, Chen AF (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am. J. Physiol. Endocrinol. Metab. 299, E110-E116.
388. Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL (1989) The pedunculopontine nucleus in Parkinson's disease. Ann. Neurol. 26, 41-46.