Therapeutic approaches in Parkinson's disease and related disorders

Journal of Neurochemistry

Volumn , Issue , 2016, Pages 346-352

  Valera, Elvira ^a   Masliah, Eliezer ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCYSTEINE; ADENOSINE A2A RECEPTOR ANTAGONIST; ALPHA SYNUCLEIN; BIIB 054; CHOLINERGIC RECEPTOR STIMULATING AGENT; EPIGALLOCATECHIN GALLATE; GLIAL CELL LINE DERIVED NEUROTROPHIC FACTOR; GLUTATHIONE; IMMUNOMODULATING AGENT; ISRADIPINE; NEUROTROPHIC FACTOR; NEURTURIN; NICOTINE; PD 01A; PD 03A; PRAMIPEXOLE; PRX 002; SARGRAMOSTIM; UBIDECARENONE; UNCLASSIFIED DRUG; VERDIPERSTAT;

ADIPOSE DERIVED STEM CELL; BRAIN DEPTH STIMULATION; CALORIC RESTRICTION; CHOLINERGIC NERVE CELL; DEGENERATIVE DISEASE; DIET RESTRICTION; DISEASE COURSE; DOPAMINERGIC NERVE CELL; DRUG EFFICACY; DRUG RESPONSE; DRUG TREATMENT FAILURE; EXERCISE; GENETIC SUSCEPTIBILITY; GENOME-WIDE ASSOCIATION STUDY; HUMAN; IMMUNOTHERAPY; MESENCHYMAL STEM CELL TRANSPLANTATION; NERVE DEGENERATION; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN SYNTHESIS; PROTEIN TARGETING; REVIEW; SHY DRAGER SYNDROME; SYNUCLEINOPATHIES; TREATMENT INDICATION;

EID: 85027942434     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/jnc.13529     Document Type: Review

References (100)

1. Ahlskog J. E. (2011) Does vigorous exercise have a neuroprotective effect in Parkinson disease? Neurology 77, 288–294.
2. Allen S. J., Watson J. J., Shoemark D. K., Barua N. U. and Patel N. K. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138, 155–175.
3. Bonifati V., Rizzu P., van Baren M. J. et al. (2003) Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259.
4. Braak H., Del Tredici K., Rub U., de Vos R. A., Jansen Steur E. N. and Braak E. (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211.
5. Caruana M., Högen T., Levin J., Hillmer A., Giese A. and Vassallo N. (2011) Inhibition and disaggregation of α-synuclein oligomers by natural polyphenolic compounds. FEBS Lett. 585, 1113–1120.
6. Clinton L. K., Blurton-Jones M., Myczek K., Trojanowski J. Q. and LaFerla F. M. (2010) Synergistic interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J. Neurosci. 30, 7281–7289.
7. Cooper J. M., Wiklander P. B., Nordin J. Z. et al. (2014) Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov. Disord. 29, 1476–1485.
8. Cotzias G. C., Papavasiliou P. S. and Gellene R. (1969) L-dopa in Parkinson's syndrome. N. Engl. J. Med. 281, 272.
9. Danzer K. M., Ruf W. P., Putcha P., Joyner D., Hashimoto T., Glabe C., Hyman B. T. and McLean P. J. (2011) Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. Faseb J. 25, 326–336.
10. Dehay B., Bourdenx M., Gorry P. et al. (2015) Targeting alpha-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. Lancet Neurol. 14, 855–866.
11. DeLong M. R. and Wichmann T. (2015) Basal ganglia circuits as targets for neuromodulation in Parkinson disease. JAMA Neurol. 72, 1354–1360.
12. Desplats P., Lee H. J., Bae E. J., Patrick C., Rockenstein E., Crews L., Spencer B., Masliah E. and Lee S. J. (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015.
13. Desplats P., Patel P., Kosberg K., Mante M., Patrick C., Rockenstein E., Fujita M., Hashimoto M. and Masliah E. (2012) Combined exposure to Maneb and Paraquat alters transcriptional regulation of neurogenesis-related genes in mice models of Parkinson's disease. Mol. Neurodegener. 7, 49.
14. Devi L. and Ohno M. (2015) A combination Alzheimer's therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice. Mol. Brain 8, 19.
15. Dua T., World Federation of Neurology, World Health Organization Programme for Neurological Diseases and Neuroscience and World Health Organization Department of Mental Health and Substance Abuse (2004) Atlas: country resources for neurological disorders 2004: results of a collaborative study of the World Health Organization and the World Federation of Neurology. Programme for Neurological Diseases and Neuroscience, Department of Mental Health and Substance Abuse, World Health Organization, Geneva.
16. Dubois B., Tolosa E., Katzenschlager R. et al. (2012) Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov. Disord. 27, 1230–1238.
17. Edwards K., Royall D., Hershey L., Lichter D., Hake A., Farlow M., Pasquier F. and Johnson S. (2007) Efficacy and safety of galantamine in patients with dementia with Lewy bodies: a 24-week open-label study. Dement. Geriatr. Cogn. Disord. 23, 401–405.
18. Evans C. G., Wisen S. and Gestwicki J. E. (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J. Biol. Chem. 281, 33182–33191.
19. Foltynie T. (2015) Can Parkinson's disease be cured by stimulating neurogenesis? J. Clin. Investig. 125, 978–980.
20. Fortin D. L., Nemani V. M., Voglmaier S. M., Anthony M. D., Ryan T. A. and Edwards R. H. (2005) Neural activity controls the synaptic accumulation of alpha-synuclein. J. Neurosci. 25, 10913–10921.
21. Freund H. J., Kuhn J., Lenartz D., Mai J. K., Schnell T., Klosterkoetter J. and Sturm V. (2009) Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch. Neurol. 66, 781–785.
22. Frost B. and Diamond M. I. (2010) Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159.
23. Games D., Valera E., Spencer B. et al. (2014) Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J. Neurosci. 34, 9441–9454.
24. Gao X., Chen H., Fung T. T., Logroscino G., Schwarzschild M. A., Hu F. B. and Ascherio A. (2007) Prospective study of dietary pattern and risk of Parkinson disease. Am. J. Clin. Nutr. 86, 1486–1494.
25. George J. M., Jin H., Woods W. S. and Clayton D. F. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15, 361–372.
26. Goedert M., Jakes R., Anthony Crowther R. and Grazia Spillantini M. (2001) Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy as alpha-synucleinopathies. Methods Mol. Med. 62, 33–59.
27. Hashimoto M., Rockenstein E., Mante M., Crews L., Bar-On P., Gage F. H., Marr R. and Masliah E. (2004) An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model. Gene Ther. 11, 1713–1723.
28. Hoban D. B., Howard L. and Dowd E. (2015) GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of Parkinson's disease. Neuroscience 303, 402–411.
29. Holloway R. G., Shoulson I., Fahn S. et al. (2004) Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch. Neurol. 61, 1044–1053.
30. Ikeda M., Mori E., Matsuo K., Nakagawa M. and Kosaka K. (2015) Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial. Alzheimers Res. Ther. 7, 4.
31. Ilijic E., Guzman J. N. and Surmeier D. J. (2011) The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson's disease. Neurobiol. Dis. 43, 364–371.
32. Ishizawa T., Mattila P., Davies P., Wang D. and Dickson D. W. (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J. Neuropathol. Exp. Neurol. 62, 389–397.
33. Iwai A., Masliah E., Yoshimoto M., De Silva R., Ge N., Kittel A. and Saitoh T. (1994) The precursor protein of non-Ab component of Alzheimer's disease amyloid (NACP) is a presynaptic protein of the central nervous system. Neuron 14, 467–475.
34. Jellinger K. A. (2003) Neuropathological spectrum of synucleinopathies. Mov. Disord. 18(Suppl 6), S2–S12.
35. Kaindlstorfer C., Sommer P., Georgievska B., Mather R. J., Kugler A. R., Poewe W., Wenning G. K. and Stefanova N. (2015) Failure of neuroprotection despite microglial suppression by delayed-start myeloperoxidase inhibition in a model of advanced multiple system atrophy: clinical implications. Neurotox. Res. 28, 185–194.
36. Kaufmann H., Freeman R., Biaggioni I. et al. (2014) Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 83, 328–335.
37. Kubo S., Hatano T., Takanashi M. and Hattori N. (2013) Can parkin be a target for future treatment of Parkinson's disease? Expert Opin. Ther. Targets 17, 1133–1144.
38. Lashuel H. A., Petre B. M., Wall J., Simon M., Nowak R. J., Walz T. and Lansbury P. T. (2002) Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J. Mol. Biol. 322, 1089–1102.
39. Lashuel H. A., Overk C. R., Oueslati A. and Masliah E. (2013) The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 14, 38–48.
40. Lee S. J., Desplats P., Sigurdson C., Tsigelny I. and Masliah E. (2010) Cell-to-cell transmission of non-prion protein aggregates. Nat. Rev. Neurol. 6, 702–706.
41. Lee P. H., Lee J. E., Kim H. S. et al. (2012) A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann. Neurol. 72, 32–40.
42. Low P. A., Robertson D., Gilman S. et al. (2014) Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 13, 268–275.
43. Lynch-Day M. A., Mao K., Wang K., Zhao M. and Klionsky D. J. (2012) The role of autophagy in Parkinson's disease. Cold Spring Harb. Perspect Med. 2, a009357.
44. Mandler M., Valera E., Rockenstein E. et al. (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 127, 861–879.
45. Masliah E., Rockenstein E., Veinbergs I., Sagara Y., Mallory M., Hashimoto M. and Mucke L. (2001) beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc. Natl Acad. Sci. USA 98, 12245–12250.
46. Maswood N., Young J., Tilmont E. et al. (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease. Proc. Natl Acad. Sci. USA 101, 18171–18176.
47. Matsumine H., Yamamura Y., Hattori N., Kobayashi T., Kitada T., Yoritaka A. and Mizuno Y. (1998) A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2). Genomics 49, 143–146.
48. NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators (2015) Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 14, 795–803.
49. Nuber S., Tadros D., Fields J. et al. (2014) Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD. Acta Neuropathol. 127, 477–494.
50. Ono K., Hasegawa K., Naiki H. and Yamada M. (2004) Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J. Neurosci. Res. 75, 742–750.
51. Paoli A., Bianco A., Damiani E. and Bosco G. (2014) Ketogenic diet in neuromuscular and neurodegenerative diseases. BioMed Res. Int. 2014, 474296.
52. Papp M. I., Kahn J. E. and Lantos P. L. (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J. Neurol. Sci. 94, 79–100.
53. Poewe W. (2010) Parkinson disease: treatment of the nonmotor symptoms of Parkinson disease. Nat. Rev. Neurol. 6, 417–418.
54. Poewe W., Seppi K., Fitzer-Attas C. J. et al. (2015) Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol. 14, 145–152.
55. Prusiner S. B., Woerman A. L., Mordes D. A. et al. (2015) Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl Acad. Sci. USA 112, E5308–E5317.
56. Quik M., Zhang D., McGregor M. and Bordia T. (2015) Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease. Biochem. Pharmacol. 97, 399–407.
57. Rascol O., Brooks D. J., Korczyn A. D., De Deyn P. P., Clarke C. E. and Lang A. E. (2000) A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. N. Engl. J. Med. 342, 1484–1491.
58. Reingold J. L., Morgan J. C. and Sethi K. D. (2007) Rivastigmine for the treatment of dementia associated with Parkinson's disease. Neuropsychiatr. Dis. Treat. 3, 775–783.
59. Renna M., Jimenez-Sanchez M., Sarkar S. and Rubinsztein D. C. (2010) Chemical inducers of autophagy that enhance the clearance of mutant proteins in neurodegenerative diseases. J. Biol. Chem. 285, 11061–11067.
60. Richardson R. M., Kells A. P., Rosenbluth K. H. et al. (2011) Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease. Mol. Ther. 19, 1048–1057.
61. Ross C. A. and Poirier M. A. (2004) Protein aggregation and neurodegenerative disease. Nat. Med. 10(Suppl), S10–S17.
62. Sacca F., Marsili A., Quarantelli M. et al. (2013) A randomized clinical trial of lithium in multiple system atrophy. J. Neurol. 260, 458–461.
63. Schapira A. H., McDermott M. P., Barone P. et al. (2013) Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. Lancet Neurol. 12, 747–755.
64. Schneeberger A., Mandler M., Mattner F. and Schmidt W. (2012) Vaccination for Parkinson's disease. Parkinsonism Relat. Disord. 18(Suppl 1), S11–S13.
65. Schneeberger A., Tierney L. and Mandler M. (2015) Active immunization therapies for Parkinson's disease and multiple system atrophy. Mov. Disord. [Epub ahead of print].
66. Schrag A., Sauerbier A. and Chaudhuri K. R. (2015) New clinical trials for nonmotor manifestations of Parkinson's disease. Mov. Disord. 30, 1490–1504.
67. Schwerk A., Altschuler J., Roch M., Gossen M., Winter C., Berg J., Kurtz A., Akyuz L. and Steiner B. (2015) Adipose-derived human mesenchymal stem cells induce long-term neurogenic and anti-inflammatory effects and improve cognitive but not motor performance in a rat model of Parkinson's disease. Regen. Med. 10, 431–446.
68. Seidl S. E., Santiago J. A., Bilyk H. and Potashkin J. A. (2014) The emerging role of nutrition in Parkinson's disease. Front. Aging Neurosci. 6, 36.
69. Sevlever D., Jiang P. and Yen S. H. (2008) Cathepsin D is the main lysosomal enzyme involved in the degradation of alpha-synuclein and generation of its carboxy-terminally truncated species. Biochemistry 47, 9678–9687.
70. Siebert M., Sidransky E. and Westbroek W. (2014) Glucocerebrosidase is shaking up the synucleinopathies. Brain 137, 1304–1322.
71. Singleton A. B., Farrer M. J. and Bonifati V. (2013) The genetics of Parkinson's disease: progress and therapeutic implications. Mov. Disord. 28, 14–23.
72. Soto C. and Estrada L. D. (2008) Protein misfolding and neurodegeneration. Arch. Neurol. 65, 184–189.
73. Spencer B., Michael S., Shen J., Kosberg K., Rockenstein E., Patrick C., Adame A. and Masliah E. (2013) Lentivirus mediated delivery of neurosin promotes clearance of wild-type alpha-synuclein and reduces the pathology in an alpha-synuclein model of LBD. Mol. Ther. 21, 31–41.
74. Spencer B., Emadi S., Desplats P. et al. (2014) ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol. Ther. 22, 1753–1767.
75. Spencer B., Valera E., Rockenstein E., Trejo-Morales M., Adame A. and Masliah E. (2015) A brain-targeted, modified neurosin (kallikrein-6) reduces alpha-synuclein accumulation in a mouse model of multiple system atrophy. Mol. Neurodegener. 10, 48.
76. Spillantini M. G. (1999) Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are alpha-synucleinopathies. Parkinsonism Relat. Disord. 5, 157–162.
77. Stefanova N., Poewe W. and Wenning G. K. (2008) Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp. Neurol. 210, 421–427.
78. Stefanova N., Georgievska B., Eriksson H., Poewe W. and Wenning G. K. (2012) Myeloperoxidase inhibition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Neurotox. Res. 21, 393–404.
79. Takeda A., Mallory M., Sundsmo M., Honer W., Hansen L. and Masliah E. (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am. J. Pathol. 152, 367–372.
80. The Multiple-System Atrophy Research Collaboration (2013) Mutations in COQ2 in familial and sporadic multiple-system atrophy. N. Engl. J. Med. 369, 233–244.
81. Toyoda Y., Erkut C., Pan-Montojo F., Boland S., Stewart M. P., Muller D. J., Wurst W., Hyman A. A. and Kurzchalia T. V. (2014) Products of the Parkinson's disease-related glyoxalase DJ-1, D-lactate and glycolate, support mitochondrial membrane potential and neuronal survival. Biol. Open 3, 777–784.
82. Tsigelny I. F., Bar-On P., Sharikov Y. et al. (2007) Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS J. 274, 1862–1877.
83. Uéda K., Fukushima H., Masliah E. et al. (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 11282–11286.
84. Valente E. M., Abou-Sleiman P. M., Caputo V. et al. (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160.
85. Valera E. and Masliah E. (2013) Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol. Ther. 138, 311–322.
86. Valera E. and Masliah E. (2015) Combination therapies: the next logical Step for the treatment of synucleinopathies? Mov. Disord. [Epub ahead of print]
87. Valera E., Ubhi K., Mante M., Rockenstein E. and Masliah E. (2014) Antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy. Glia 62, 317–337.
88. Valera E., Mante M., Anderson S., Rockenstein E. and Masliah E. (2015) Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson's disease. J. Neuroinflammation 12, 93.
89. Voss K., Combs B., Patterson K. R., Binder L. I. and Gamblin T. C. (2012) Hsp70 alters tau function and aggregation in an isoform specific manner. Biochemistry 51, 888–898.
90. Wakabayashi K., Matsumoto K., Takayama K., Yoshimoto M. and Takahashi H. (1997) NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson's disease. Neurosci. Lett. 239, 45–48.
91. Wakabayashi K., Hayashi S., Kakita A., Yamada M., Toyoshima Y., Yoshimoto M. and Takahashi H. (1998a) Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol. 96, 445–452.
92. Wakabayashi K., Yoshimoto M., Tsuji S. and Takahashi H. (1998b) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci. Lett. 249, 180–182.
93. Warren Olanow C., Bartus R. T., Baumann T. L. et al. (2015) Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann. Neurol. 78, 248–257.
94. Wichmann T. and Delong M. R. (2011) Deep-brain stimulation for basal ganglia disorders. Basal Ganglia 1, 65–77.
95. Winklhofer K. F. (2007) The parkin protein as a therapeutic target in Parkinson's disease. Expert Opin. Ther. Targets 11, 1543–1552.
96. Winner B., Jappelli R., Maji S. K. et al. (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl Acad. Sci. USA 108, 4194–4199.
97. Wobst H. J., Sharma A., Diamond M. I., Wanker E. E. and Bieschke J. (2015) The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett. 589, 77–83.
98. Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators, Kieburtz K., Tilley B. C. et al. (2015) Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA 313, 584–593.
99. Yoritaka A., Kawajiri S., Yamamoto Y., Nakahara T., Ando M., Hashimoto K., Nagase M., Saito Y. and Hattori N. (2015) Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease. Parkinsonism Relat. Disord. 21, 911–916.
100. Zimprich A., Biskup S., Leitner P. et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607.