Ghrelin is neuroprotective in Parkinson's disease: Molecular mechanisms of metabolic neuroprotection

Therapeutic Advances in Endocrinology and Metabolism

Volumn 4, Issue 1, 2013, Pages 25-36

  Bayliss, Jacqueline A ^a   Andrews, Zane B ^a  

^a MONASH UNIVERSITY   (Australia)

Author keywords

AMPK; calorie restriction; ghrelin; mitophagy; neuroprotection; Parkinson's disease; substantia nigra

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; ALPHA SYNUCLEIN; CABERGOLINE; CASPASE; CELL PROTEIN; DOPAMINE; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; GHRELIN; GHRELIN AGONIST; GHRELIN RECEPTOR; GLUCOSE; GUANIDINOPROPIONIC ACID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LEUCINE RICH REPEAT KINASE 2; LEVODOPA; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; PARKIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PINK1 PROTEIN; REACTIVE OXYGEN METABOLITE; SIRTUIN 1; UNCLASSIFIED DRUG;

APPETITE; ARTICLE; AUTOPHAGOSOME; AUTOPHAGY; BODY WEIGHT; CACHEXIA; CALORIC RESTRICTION; CELL DAMAGE; CELL INCLUSION; CELL SURVIVAL; DIABETES MELLITUS; DISEASE COURSE; DISEASE PREDISPOSITION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DOPAMINERGIC NERVE CELL; DRUG CYTOTOXICITY; DYSKINESIA; ELECTRON TRANSPORT; ENERGY METABOLISM; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; GASTROINTESTINAL HEMORRHAGE; GENE; GENE MUTATION; GENE OVEREXPRESSION; GLUCOSE BLOOD LEVEL; GLUCOSE UTILIZATION; HORMONE ACTION; HUMAN; HYPOTENSION; LEARNING; LRRK2 GENE; MEMORY; METABOLIC NEUROPROTECTION; METABOLIC REGULATION; MICROGLIA; MITOCHONDRIAL BIOGENESIS; MITOCHONDRION; MITOPHAGY; MOLECULARLY TARGETED THERAPY; NAUSEA; NERVE DEGENERATION; NEUROPROTECTION; OBESITY; PARKINSON DISEASE; PRIORITY JOURNAL; TRANQUILIZING ACTIVITY;

EID: 84874771458     PISSN: 20420188     EISSN: 20420196     Source Type: Journal    
DOI: 10.1177/2042018813479645     Document Type: Article

References (100)

1. Abbott R. Ross G. White L. Nelson J. Masaki K. Tanner C. et al. (2002) Midlife adiposity and the future risk of Parkinson's disease. Neurology 59: 1051–1057.
2. Abou-Sleiman P. Muqit M. Wood N. (2006) Expanding insights of mitochondrial dysfunction in Parkinson's disease. Nat Rev Neurosci 7: 207–219.
3. Alam M. Schmidt W. (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136: 317–324.
4. Alvarez-Erviti L. Seow Y. Schapira A. Gardiner C. Sargent I. Wood M. et al. (2011) Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis 42: 360–367.
5. Andrews Z. (2011) The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci 34: 31–40.
6. Andrews Z. Diano S. Horvath T. (2005 a) Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Nat Rev Neurosci 6: 829–840.
7. Andrews Z. Erion D. Beiler R. Liu Z. Abizaid A. Zigman J. et al. (2009) Ghrelin promotes and protects nigrostriatal dopamine function via a UCP2-dependent mitochondrial mechanism. J Neurosci 29: 14057–14065.
8. Andrews Z. Horvath B. Barnstable C. Elsworth J. Yang L. Beal M. et al. (2005 b) Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease. J Neurosci 25: 184–191.
9. Andrews Z. Liu Z. Walllingford N. Erion D. Borok E. Friedman J. et al. (2008) UCP 2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454: 846–851.
10. Banati R. Gehrmann J. Schubert P. Kreutzberg G. (1993) Cytotoxicity of microglia. Glia 7: 111–118.
11. Bergeron R. Ren J. Cadman K. Moore I. Perret P. Pypaert M. et al. (2001) Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab 281: E1340–E1346.
12. Bonifati V. (2007) LRRK 2 low-penetrance mutations (Gly2019Ser) and risk alleles (Gly2385Arg)-linking familial and sporadic Parkinson's disease. Neurochem Res 32: 1700–1708.
13. Braak H. de Vos R. Bohl J. Del Tredici K. (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 396: 67–72.
14. Briggs D. Enriori P. Lemus M. Cowley M. Andrews Z. (2010) Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151: 4745–4755.
15. Briggs D. Lemus M. Kua E. Andrews Z. (2011) Diet-induced obesity attenuates fasting-induced hyperphagia. J Neuroendocrinol 23: 620–626.
16. Burguillos M. Deierborg T. Kavanagh E. Persson A. Hajji N. Garcia-Quintanilla A. et al. (2011) Caspase signalling controls microglia activation and neurotoxicity. Nature 472: 319–324.
17. Canto C. Auwerx J. (2009) PGC-1alpha, SIRT 1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20: 98–105.
18. Canto C. Gerhart-Hines Z. Feige J. Lagouge M. Noriega L. Milne J. et al. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT 1 activity. Nature 458: 1056–1060.
19. Carling D. Aguan K. Woods A. Verhoeven A. Beri R. Brennan C. et al. (1994) Mammalian AMP-activated protein kinase is homologous to yeast and plant protein kinases involved in the regulation of carbon metabolism. J Biol Chem 269: 11442–11448.
20. Chartier-Harlin M. Kachergus J. Roumier C. Mouroux V. Douay X. Lincoln S. et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364: 1167–1169.
21. Chen H. Zhang S. Hernan M. Willett W. Ascherio A. (2003) Weight loss in Parkinson's disease. Ann Neurol 53: 676–679.
22. Choi J. Jang E. Park C. Kang J. (2005) Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med 38: 806–816.
23. Colman R. Anderson R. Johnson S. Kastman E. Kosmatka K. Beasley T. et al. (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325: 201–204.
24. Conti B. Sugama S. Lucero J. Winsky-Sommerer R. Wirz S. Maher P. et al. (2005) Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity. J Neurochem 93: 493–501.
25. Crute B. Seefeld K. Gamble J. Kemp B. Witters L. (1998) Functional domains of the alpha 1 catalytic subunit of the AMP-activated protein kinase. J Biol Chem 273: 35347–35354.
26. Damian M. Marie J. Leyris J. Fehrentz J. Verdie P. Martinez J. et al. (2012) High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. J Biol Chem 287: 3630–3641.
27. Davalos D. Grutzendler J. Yang G. Kim J. Zuo Y. Jung S. et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8 (6): 752–758.
28. Diano S. Farr S. Benoit S. McNay E. da Silva I. Horvath B. et al. (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9: 381–388.
29. Dickson D. Lee S. Mattiace L. Yen S. Brosnan C. (1993) Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia 7 (1): 75–83.
30. Dong J. Song N. Xie J. Jiang H. (2009) Ghrelin antagonized 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. J Mol Neurosci 37: 182–189.
31. Edwards L. Quigley E. Pfeiffer R. (1992) Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology 42: 726–732.
32. Feany M. Bender W. (2000) A Drosophila model of Parkinson's disease. Nature 404: 394–398.
33. Fiszer U. Michalowska M. Baranowska B. Wolinska-Witort E. Jeske W. Jethon M. et al. (2010) Leptin and ghrelin concentrations and weight loss in Parkinson's disease. Acta Neurol Scand 121: 230–236.
34. Friedman L. Lachenmayer M. Wang J. He L. Poulose S. Komatsu M. et al. (2012) Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK 2 in the brain. J Neurosci 32: 7585–7593.
35. Gahete M. Cordoba-Chacon J. Kineman R. Luque R. Castano J. (2011) Role of ghrelin system in neuroprotection and cognitive functions: implications in Alzheimer's disease. Peptides 32: 2225–2228.
36. Godwin-Austen R. Tomlinson E. Frears C. Kok H. (1969) Effects of L-dopa in Parkinson's disease. Lancet 2: 165–168.
37. Gomez-Suaga P. Luzon-Toro B. Churamani D. Zhang L. Bloor-Young D. Patel S. et al. (2012) Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP. Hum Mol Genet 21: 511–525.
38. Gualillo O. Lago F. Gomez-Reino J. Casanueva F. Dieguez C. (2003) Ghrelin, a widespread hormone: insights into molecular and cellular regulation of its expression and mechanism of action. FEBS Lett 552: 105–109.
39. Hansen C. Angot E. Bergstrom A. Steiner J. Pieri L. Paul G. et al. (2011) alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121: 715–725.
40. Hardie D. Ross F. Hawley S. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13: 251–262.
41. Holst B. Holliday N. Bach A. Elling C. Cox H. Schwartz T. (2004) Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 279: 53806–53817.
42. Horvath T. Erion D. Elsworth J. Roth R. Shulman G. Andrews Z. (2011) GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function. Neurobiol Dis 43: 152–162.
43. Hurley M. Patel P. Jackson M. Smith L. Rose S. Jenner P. (2007) Striatal leucine-rich repeat kinase 2 mRNA is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned common marmosets (Callithrix jacchus) with L-3, 4-dihydroxyphenylalanine methyl ester-induced dyskinesia. Eur J Neurosci 26: 171–177.
44. Iglesias M. Furler S. Cooney G. Kraegen E. Ye J. (2004) AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo. Diabetes 53: 1649–1654.
45. Jiang H. Betancourt L. Smith R. (2006) Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20: 1772–1785.
46. Jiang H. Li L. Wang J. Xie J. (2008) Ghrelin antagonizes MPTP-induced neurotoxicity to the dopaminergic neurons in mouse substantia nigra. Exp Neurol 212: 532–537.
47. Jorgensen S. Viollet B. Andreelli F. Frosig C. Birk J. Schjerling P. et al. (2004) Knockout of the alpha 2 but not alpha 1 5′-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. J Biol Chem 279: 1070–1079.
48. Keranen T. Kaakkola S. Sotaniemi K. Laulumaa V. Haapaniemi T. Jolma T. et al. (2003) Economic burden and quality of life impairment increase with severity of PD. Parkinsonism Relat Disord 9: 163–168.
49. Kern A. Albarran-Zeckler R. Walsh H. Smith R. (2012) Apo-ghrelin receptor forms heteromers with DRD 2 in hypothalamic neurons and is essential for anorexigenic effects of DRD 2 agonism. Neuron 73: 317–332.
50. Kim J. Kundu M. Viollet B. Guan K. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13: 132–141.
51. Kitada T. Asakawa S. Hattori N. Matsumine H. Yamamura Y. Minoshima S. et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392: 605–608.
52. Kuo Y. Li Z. Jiao Y. Gaborit N. Pani A. Orrison B. et al. (2010) Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated alpha-synuclein gene mutations precede central nervous system changes. Hum Mol Genet 19: 1633–1650.
53. Lebouvier T. Neunlist M. Bruley des Varannes S. Coron E. Drouard A. N'Guyen J. et al. (2010) Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PloS ONE 5 (9): e12728.
54. Lee S. Kim Y. Li E. Park S. (2012) Ghrelin protects spinal cord motoneurons against chronic glutamate excitotoxicity by inhibiting microglial activation. Korean J Physiol Pharmacol 16: 43–48.
55. Lesser R. Fahn S. Snider S. Cote L. Isgreen W. Barrett R. (1979) Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 29: 1253–1260.
56. Leung P. Chow K. Lau P. Chu K. Chan C. Cheng C. et al. (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19: 1011–1022.
57. Li J. Englund E. Holton J. Soulet D. Hagell P. Lees A. et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host- to-graft disease propagation. Nat Med 14: 501–503.
58. Lin M. Beal M. (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787–795.
59. Lin X. Parisiadou L. Gu X. Wang L. Shim H. Sun L. et al. (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant alpha-synuclein. Neuron 64: 807–827.
60. Logroscino G. Sesso H. Paffenbarger R. Lee I. (2007) Body mass index and risk of Parkinson's disease: a prospective cohort study. Am J Epidemiol 166: 1186–1190.
61. Lopez-Lluch G. Hunt N. Jones B. Zhu M. Jamieson H. Hilmer S. et al. (2006) Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 103: 1768–1773.
62. Lutter M. Sakata I. Osborne-Lawrence S. Rovinsky S. Anderson J. Jung S. et al. (2008) The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 11: 752–753.
63. Mann V. Cooper J. Krige D. Daniel S. Schapira A. Marsden C. (1992) Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. Brain 115: 333–342.
64. Marongiu R. Spencer B. Crews L. Adame A. Patrick C. Trejo M. et al. (2009) Mutant Pink 1 induces mitochondrial dysfunction in a neuronal cell model of Parkinson's disease by disturbing calcium flux. J Neurochem 108: 1561–1574.
65. Melamed E. Offen D. Shirvan A. Djaldetti R. Barzilai A. Ziv I. (1998) Levodopa toxicity and apoptosis. Ann Neurol 44(3 Suppl. 1): S149–S154.
66. Moon M. Kim H. Hwang L. Seo J. Kim S. Hwang S. et al. (2009) Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease by blocking microglial activation. Neurotox Res 15: 332–347.
67. Mudo G. Makela J. Di Liberto V. Tselykh T. Olivieri M. Piepponen P. et al. (2012) Transgenic expression and activation of PGC-1alpha protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease. Cell Mol Life Sci 69: 1153–1165.
68. Murakami N. Hayashida T. Kuroiwa T. Nakahara K. Ida T. Mondal M. et al. (2002) Role for central ghrelin in food intake and secretion profile of stomach ghrelin in rats. J Endocrinol 174: 283–288.
69. Neary N. Small C. Wren A. Lee J. Druce M. Palmieri C. et al. (2004) Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 89: 2832–2836.
70. Ng C. Guan M. Koh C. Ouyang X. Yu F. Tan E. et al. (2012) AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson's disease. J Neurosci 32: 14311–14317.
71. O'Neill H. Maarbjerg S. Crane J. Jeppesen J. Jorgensen S. Schertzer J. et al. (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U S A 108: 16092–16097.
72. Parihar M. Parihar A. Fujita M. Hashimoto M. Ghafourifar P. (2008) Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci 65: 1272–1284.
73. Perreault M. Istrate N. Wang L. Nichols A. Tozzo E. Stricker-Krongrad A. (2004) Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss. Int J Obes Relat Metab Disord 28: 879–885.
74. Plowey E. Cherra S. Liu Y. Chu C. (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105: 1048–1056.
75. Politis M. Wu K. Molloy S. G Bain P. Chaudhuri K. Piccini P. (2010) Parkinson's disease symptoms: the patient's perspective. Mov Disord 25: 1646–1651.
76. Qiu X. Brown K. Hirschey M. Verdin E. Chen D. (2010) Calorie restriction reduces oxidative stress by SIRT3-mediated SOD 2 activation. Cell Metab 12: 662–667.
77. Rock R. Gekker G. Hu S. Sheng W. Cheeran M. Lokensgard J. et al. (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17: 942–964.
78. Saha A. Ninkina N. Hanger D. Anderton B. Davies A. Buchman V. (2000) Induction of neuronal death by alpha-synuclein. Eur J Neurosci 12: 3073–3077.
79. Salome N. Haage D. Perrissoud D. Moulin A. Demange L. Egecioglu E. et al. (2009) Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats. Eur J Pharmacol 612: 167–173.
80. Shin J. Ko H. Kang H. Lee Y. Lee Y. Pletinkova O. et al. (2011) PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 144: 689–702.
81. Siddiqui A. Chinta S. Mallajosyula J. Rajagopolan S. Hanson I. Rane A. et al. (2012) Selective binding of nuclear alpha-synuclein to the PGC1alpha promoter under conditions of oxidative stress may contribute to losses in mitochondrial function: implications for Parkinson's disease. Free Radic Biol Med 53: 993–1003.
82. St-Pierre J. Drori S. Uldry M. Silvaggi J. Rhee J. Jager S. et al. (2006) Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127: 397–408.
83. Starkstein S. Preziosi T. Robinson R. (1991) Sleep disorders, pain, and depression in Parkinson's disease. Eur Neurol 31: 352–355.
84. Suliman H. Welty-Wolf K. Carraway M. Tatro L. Piantadosi C. (2004) Lipopolysaccharide induces oxidative cardiac mitochondrial damage and biogenesis. Cardiovasc Res 64: 279–288.
85. Sun Y. Butte N. Garcia J. Smith R. (2008) Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 149: 843–850.
86. Sung Y. Kim S. Hong H. Park C. Shin M. Kim C. et al. (2012) Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson's disease mice. Life Sci, in press.
87. Tschop M. Smiley D. Heiman M. (2000) Ghrelin induces adiposity in rodents. Nature 407: 908–913.
88. Unger M. Moller J. Mankel K. Eggert K. Bohne K. Bodden M. et al. (2011) Postprandial ghrelin response is reduced in patients with Parkinson's disease and idiopathic REM sleep behaviour disorder: a peripheral biomarker for early Parkinson's disease? J Neurol 258: 982–990.
89. Uversky V. (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103: 17–37.
90. Vives-Bauza C. Zhou C. Huang Y. Cui M. de Vries R. Kim J. et al. (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107: 378–383.
91. Wahlqvist M. Lee M. Hsu C. Chuang S. Lee J. Tsai H. (2012) Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord 18: 753–758.
92. Winder W. Holmes B. Rubink D. Jensen E. Chen M. Holloszy J. (2000) Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 88: 2219–2226.
93. Yamauchi T. Kamon J. Minokoshi Y. Ito Y. Waki H. Uchida S. et al. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8: 1288–1295.
94. Yang J. Brown M. Liang G. Grishin N. Goldstein J. (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132: 387–396.
95. Zgaljardic D. Foldi N. Borod J. (2004) Cognitive and behavioral dysfunction in Parkinson's disease: neurochemical and clinicopathological contributions. J Neural Transm 111: 1287–1301.
96. Zhao T. Liang G. Li R. Xie X. Sleeman M. Murphy A. et al. (2010) Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci U S A 107: 7467–7472.
97. Zheng B. Liao Z. Locascio J. Lesniak K. Roderick S. Watt M. et al. (2010) PGC-1alpha, a potential therapeutic target for early intervention in Parkinson's disease. Sci Transl Med 2 (52): 52ra73.
98. Zhu X. Cao Y. Voogd K. Steiner D. (2006) On the processing of proghrelin to ghrelin. J Biol Chem 281: 38867–38870.
99. Zoccolella S. Savarese M. Lamberti P. Manni R. Pacchetti C. Logroscino G. (2011) Sleep disorders and the natural history of Parkinson's disease: the contribution of epidemiological studies. Sleep Med Rev 15: 41–50.
100. Zong H. Ren J. Young L. Pypaert M. Mu J. Birnbaum M. et al. (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 99: 15983–15987.