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Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates

Nature Reviews Neuroscience volume 12, pages 359–366 (2011)Cite this article

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Abstract

Ageing is the greatest risk factor for the development of Parkinson's disease. However, the current dogma holds that cellular mechanisms that are associated with ageing of midbrain dopamine neurons and those that are related to dopamine neuron degeneration in Parkinson's disease are unrelated. We propose, based on evidence from studies of non-human primates, that normal ageing and the degeneration of dopamine neurons in Parkinson's disease are linked by the same cellular mechanisms and, therefore, that markers of cellular risk factors accumulate with age in a pattern that mimics the pattern of degeneration observed in Parkinson's disease. We contend that ageing induces a pre-parkinsonian state, and that the cellular mechanisms of dopamine neuron demise during normal ageing are accelerated or exaggerated in Parkinson's disease through a combination of genetic and environmental factors.

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Figure 1: Regional differences in vulnerability to degeneration in Parkinson's disease and models of parkinsonism.
Figure 2: The pattern of ageing-related changes in markers of cellular mechanisms.
Figure 3: The stochastic acceleration hypothesis.

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References

  1. Bennett, D. A. et al. Prevalence of parkinsonian signs and associated mortality in a community population of older people. N. Engl. J. Med. 334, 71–76 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Morens, D. M. et al. Epidemiologic observations on Parkinson's disease: incidence and mortality in a prospective study of middle aged men. Neurology 46, 1044–1050 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Tanner, C. M. & Goldman, S. M. Epidemiology of Parkinson's disease. Neurol. Clin. 14, 317–335 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991).

    Article  PubMed  Google Scholar 

  5. Gibb, W. R. & Lees, A. J. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease. J. Neurol. Neurosurg. Psychiatr. 54, 388–396 (1991).

    Article  CAS  Google Scholar 

  6. Hornykiewicz, O. 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 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Kish, S. J., Shannak, K., Rajput, A., Deck, J. H. & Hornykiewicz, O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson's disease. J. Neurochem. 58, 642–648 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 122, 1437–1448 (1999).

    Article  PubMed  Google Scholar 

  9. Chiueh, C. C., Burns, R. S., Markey, S. P., Jacobowitz, D. M. & Kopin, I. J. Primate model of parkinsonism: selective lesion of nigrostriatal neurons by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces an extrapyramidal syndrome in rhesus monkeys. Life Sci. 36, 213–218 (1985).

    Article  CAS  PubMed  Google Scholar 

  10. German, D. C., Dubach, M., Askari, S., Speciale, S. G. & Bowden, D. M. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost? Neuroscience 24, 161–174 (1988).

    Article  CAS  PubMed  Google Scholar 

  11. Kitt, C. A., Cork, L. C., Eidelberg, F., Joh, T. H. & Price, D. L. Injury of nigral neurons exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a tyrosine hydroxylase immuunocytochemical study in monkey. Neuroscience 17, 1089–1103 (1986).

    Article  CAS  PubMed  Google Scholar 

  12. Schnieder, J. S., Yuwiler, A. & Markham, C. H. Selective loss of subpopulations of ventral mesencephalic dopaminergic neurons in the monkey following exposure to MPTP. Brain Res. 411, 144–150 (1987).

    Article  Google Scholar 

  13. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nature Neurosci. 3, 1301–1306 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. German, D. C. et al. The neurotoxin MPTP causes degeneration of specific nucleus A8, A9 and A10 dopaminergic neurons in the mouse. Neurodegeneration 5, 299–312 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Grant, R. J. & Clarke, P. B. Susceptibility of ascending dopamine projections to 6-hydroxydopamine in rats: effect of hypothermia. Neuroscience 115, 1281–1294 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Emborg, M. E. et al. Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J. Comp. Neurol. 401, 253–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, Z. et al. Motor slowing and parkinsonian signs in aging rhesus monkeys mirror human aging. J. Gerontol. A Biol. Sci. Med. Sci. 55, B473–B480 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Chu, Y. & Kordower, J. H. Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson's disease? Neurobiol. Dis. 25, 134–149 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Kanaan, N. M., Kordower, J. H. & Collier, T. J. 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 (2007).

    Article  PubMed  Google Scholar 

  20. Kanaan, N. M., Kordower, J. H. & Collier, T. J. 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 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kanaan, N. M., Kordower, J. H. & Collier, T. J. Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys. Neurobiol. Aging 31, 937–952 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kanaan, N. M., Kordower, J. H. & Collier, T. J. Age and region-specific responses of microglia, but not astrocytes, suggest a role in selective vulnerability of dopamine neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in monkeys. Glia 56, 1199–1214 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Andersen, A. H., Zhang, Z., Zhang, M., Gash, D. M. & Avison, M. J. Age-associated changes in rhesus CNS composition identified by MRI. Brain Res. 829, 90–98 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Collier, T. J. et al. Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol. Dis. 26, 56–65 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Irwin, I. et al. Aging and the nigrostriatal dopamine system: a non-human primate study. Neurodegeneration 3, 251–265 (1994).

    CAS  PubMed  Google Scholar 

  26. McCormack, A. L. et al. Aging of the nigrostriatal system in the squirrel monkey. J. Comp. Neurol. 471, 387–395 (2004).

    Article  PubMed  Google Scholar 

  27. Pakkenberg, H., Andersen, B. B., Burns, R. S. & Pakkenberg, B. A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res. 693, 201–206 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Irizarry, M. C. et al. Nigral and cortical Lewy bodies and dystrophic nigral neurites in Parkinson's disease and cortical Lewy body disease contain α-synuclein immunoreactivity. J. Neuropathol. Exp. Neurol. 57, 334–337 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Spillantini, M. G. et al. α-synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Ross, O. A. et al. Genomic investigation of α-synuclein multiplication and parkinsonism. Ann. Neurol. 63, 743–750 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Jellinger, K. A. Lewy body-related α-synucleinopathy in the aged human brain. J. Neural Transm. 111, 1219–1235 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Li, W. et al. Stabilization of α-synuclein protein with ageing and familial Parkinson's disease-linked A53T mutation. J. Neurosci. 24, 7400–7409 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Maingay, M., Romero-Ramos, M., Carta, M. & Kirik, D. Ventral tegmental area dopamine neurons are resistant to human mutant α-synuclein overexpression. Neurobiol. Dis. 23, 522–532 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet. 25, 302–305 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Lee, H. J., Khoshaghideh, F., Patel, S. & Lee, S. J. Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci. 24, 1888–1896 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. α-synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Chu, Y., Dodiya, H., Aebischer, P., Olanow, C. W. & Kordower, J. H. Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to α-synuclein inclusions. Neurobiol. Dis. 35, 385–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Hald, A. & Lotharius, J. Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp. Neurol. 193, 279–290 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Jenner, P. Oxidative stress in Parkinson's disease. Ann. Neurol. 53, S26–S36 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Brunk, U. T. & Terman, A. The mitochondrial–lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur. J. Biochem. 269, 1996–2002 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Brunk, U. T. & Terman, A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic. Biol. Med. 33, 611–619 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Terman, A. & Brunk, U. T. Lipofuscin: mechanisms of formation and increase with age. APMIS 106, 265–276 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Terman, A., Gustafsson, B. & Brunk, U. K. Mitochondrial damage and intralysosomal degradation in cellular aging. Mol. Aspects Med. 27, 471–482 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Siddiqi, Z. A. & Peters, A. The effect of aging on pars compacta of the substantia nigra in rhesus monkey. J. Neuropathol. Exp. Neurol. 58, 903–920 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Beach, T. G. et al. Substantia nigra Marinesco bodies are associated with decreased striatal expression of dopaminergic markers. J. Neuropathol. Exp. Neurol. 63, 329–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Yuen, P. & Baxter, D. W. The morphology of Marinesco bodies (paranucleolar corpuscles) in the melanin-pigmented nuclei of the brainstem. J. Neurol. Neurosurg. Psychiatr. 26, 178–183 (1963).

    Article  CAS  Google Scholar 

  49. Strehler, B. L. On the histochemistry and ultrastructure of age pigment. Adv. Gerontol. Res. 18, 343–384 (1964).

    CAS  PubMed  Google Scholar 

  50. Ulfig, N. Altered lipofuscin pigmentation in the basal nucleus (Meynert) in Parkinson's disease. Neurosci. Res. 6, 456–462 (1989).

    Article  CAS  PubMed  Google Scholar 

  51. Elsworth, J. D., Deutch, A. Y., Redmond, D. E. Jr, Sladek, J. R. Jr & Roth, R. H. Differential responsiveness to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in sub-regions of the primate substantia nigra and striatum. Life Sci. 40, 193–202 (1987).

    Article  CAS  PubMed  Google Scholar 

  52. Meredith, G. E. et al. Lysosomal malfunction accompanies α-synuclein aggregation in a progressive mouse model of Parkinson's disease. Brain Res. 956, 156–165 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Asanuma, M., Miyazaki, I., Diaz-Corrales, F. J. & Ogawa, N. Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism. Acta Med. Okayama 58, 221–233 (2004).

    CAS  PubMed  Google Scholar 

  54. Cantuti-Castelvetri, I., Shukitt-Hale, B. & Joseph, J. A. Dopamine neurotoxicity: age-dependent behavioral and histological effects. Neurobiol. Aging 24, 697–706 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Caudle, W. M. et al. Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J. Neurosci. 27, 8138–8148 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gonzalez-Hernandez, T., Barroso-Chinea, P., De La Cruz Muros, I., Del Mar Perez-Delgado, M. & Rodriguez, M. Expression of dopamine and vesicular monoamine transporters and differential vulnerability of mesostriatal dopaminergic neurons. J. Comp. Neurol. 479, 198–215 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Banati, R. B., Daniel, S. E. & Blunt, S. B. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov. Disord. 13, 221–227 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Mirza, B., Hadberg, H., Thomsen, P. & Moos, T. The absence of reactive astrocytosis is indicative of a unique inflammatory process in Parkinson's disease. Neuroscience 95, 425–432 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Imamura, K. et al. Distribution of major histocompatibility complex class II-positive microglia and cytokine profile of Parkinson's disease brains. Acta Neuropathol. 106, 518–526 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988).

    Article  CAS  PubMed  Google Scholar 

  61. Mogi, M. et al. Caspase activites and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from parkinsonian brain. J. Neural Transm. 107, 335–341 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Castano, A., Herrera, A. J., Cano, J. & Machado, A. Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system. J. Neurochem. 70, 1584–1592 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Wu, D. C. et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. J. Neurosci. 22, 1763–1771 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Alladi, P. A. et al. Absence of age-related changes in nigral dopaminergic neurons of Asian Indians: relevance to lower incidence of Parkinson's disease. Neuroscience 159, 236–245 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Chu, Y., Kompliti, K., Cochran, E. J., Mufson, E. J. & Kordower, J. H. Age-related decrease in Nurr1 immunoreactivity in the human substantia nigra. J. Comp. Neurol. 450, 203–214 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Kubis, N. et al. Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 123, 366–373 (2000).

    Article  PubMed  Google Scholar 

  67. Gerhardt, G. A., Cass, W. A., Yi, A., Zhang, Z. & Gash, D. M. Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J. Neurochem. 80, 168–177 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Chan, C. S., Gertler, T. S. & Surmeier, D. J. Calcium homeostasis, selective vulnerability and Parkinson's disease. Trends Neurosci. 32, 249–256 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liang, C. L., Sinton, C. M., Sonsalla, P. K. & German, D. C. Midbrain dopaminergic neurons in the mouse that contain calbindin-D28k exhibit reduced vulnerability to MPTP-induced neurodegeneration. Neurodegeneration 5, 313–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  70. Mosharov, E. V. et al. Interplay between cytosolic dopamine, calcium, and α-synuclein causes selective death of substantia nigra neurons. Neuron 62, 218–229 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson's disease. Nature Genet. 38, 515–517 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genet. 38, 518–520 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Morfini, G. A. et al. Axonal transport defects in neurodegenerative diseases. J. Neurosci. 29, 12776–12786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ren, Y., Liu, W., Jiang, H., Jiang, Q. & Feng, J. Selective vulnerability of dopaminergic neurons to microtubule depolymerization. J. Biol. Chem. 280, 34105–34112 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Chauhan, N. B., Siegel, G. J. & Lee, J. M. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain. J. Chem. Neuroanat. 21, 277–288 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Howells, D. W. et al. Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra. Exp. Neurol. 166, 127–135 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Parain, K. et al. Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. Neuroreport 10, 557–561 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Chung, C. Y. et al. Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum. Mol. Genet. 14, 1709–1725 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Greene, J. G., Dingledine, R. & Greenamyre, J. T. Gene expression profiling of rat midbrain dopamine neurons: implications for selective vulnerability in parkinsonism. Neurobiol. Dis. 18, 19–31 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Ji, K.-A. et al. Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex. Glia 56, 1039–1047 (2008).

    Article  PubMed  Google Scholar 

  81. Lewers, J. C. et al. Consequences of impaired purine recycling in dopaminergic neurons. Neuroscience 152, 761–772 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Liss, B. et al. K-ATP channels promote the differential degeneration of dopaminergic midbrain neurons. Nature Neurosci. 8, 1742–1751 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Nafia, I. et al. Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction. J. Neurochem. 105, 484–496 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Villar-Cheda, B. et al. Nigral and striatal expression of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson's disease. Eur. J. Neurosci. 32, 1695–1706 (2010).

    Article  PubMed  Google Scholar 

  85. Wang, H.-L. & Morales, M. Corticotropin-releasing factor binding protein within the ventral tegmental area is expressed in a subset of dopaminergic neurons. J. Comp. Neurol. 509, 302–318 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Coleman, P., Finch, C. & Joseph, J. The need for multiple time points in aging studies. Neurobiol. Aging 25, 3–4 (1994).

    Article  Google Scholar 

  87. Eshius, S. A. & Leenders, K. L. Parkinson's Disease: Symptoms and Age Dependency in Functional Neurobiology of Aging (eds Hof, P. R. & Mobbs, C. V.) 675–688 (Academic Press, San Diego, 2001).

    Chapter  Google Scholar 

  88. Diedrich, N. J. H., Moore, C. G., Leurgans, S. E., Chmura, T. A. & Goetz, C. G. Parkinson disease with old-age onset: a comparative study with subjects with middle-age onset. Arch. Neurol. 60, 529–533 (2003).

    Article  Google Scholar 

  89. Hely, M. A. et al. Age at onset: the major determinant of outcome in Parkinson's disease. Acta Neurol. Scand. 92, 455–463 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Jankovic, J. & Kapadia, A. S. Functional decline in Parkinson's disease. Arch. Neurol. 58, 1611–1615 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Muller, W. E. & Pedigo, N. W. Jr. Brain aging: a risk factor of neurodegenerative disorders and a target for therapeutic intervention. Life Sci. 55, 1975–1976 (1994).

    Article  CAS  PubMed  Google Scholar 

  92. Thal, D. R., Del Tredici, K. & Braak, H. Neurodegeneration in normal brain aging and disease. Sci. Aging Knowl. Environ. 2004, pe26 (2004).

    Article  Google Scholar 

  93. Calne, D. B. & Langston, J. W. Aetiology of Parkinson's disease. Lancet 2, 1457–1479 (1983).

    Article  CAS  PubMed  Google Scholar 

  94. Carvey, P. M., Punati, A. & Newman, M. B. Progressive dopamine neuron loss in Parkinson's disease: the multiple hit hypothesis. Cell Transplant. 15, 239–250 (2006).

    Article  PubMed  Google Scholar 

  95. Sulzer, D. Multiple hit hypothesis for dopamine neuron loss in Parkinson's disease. Trends Neurosci. 30, 244–250 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Chu, Y. et al. Nurr1 in Parkinson's disease and related disorders. J. Comp. Neurol. 494, 495–514 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kastner, A., Hirsch, E. C., Herrero, M. T., Javoy-Agid, F. & Agid, Y. 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 (1993).

    Article  CAS  PubMed  Google Scholar 

  98. Miller, G. W. et al. Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson's disease. Exp. Neurol. 156, 138–148 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Muthane, U., Yasha, T. C. & Shankar, S. K. Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India. Ann. Neurol. 43, 283–287 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Haycock, J. W. et al. Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum. J. Neurochem. 87, 574–585 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Kish, S. J., Shannak, K. & Hornykiewicz, O. 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 (1988).

    Article  CAS  PubMed  Google Scholar 

  102. Joyce, J. N. The Basal Ganglia Dopaminergic Systems in Normal Aging and Parkinson's Disease in Functional Neurobiology of Aging (eds Hof. P. R. & Mobbs, C. V.) 689–709 (Academic Press, San Diego,2001).

    Chapter  Google Scholar 

  103. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  104. Zeng, B. Y., Medhurst, A. D., Jackson, M., Rose, S. & Jenner, P. Proteasomal activity in brain differs between species and brain regions and changes with age. Mech. Ageing Dev. 126, 760–766 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Goldman, J. E., Yen, S. H., Chiu, F. C. & Peress, N. S. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science 221, 1082–1084 (1983).

    Article  CAS  PubMed  Google Scholar 

  106. McNaught, K. S., Belizaire, R., Isacson, O., Jenner, P. & Olanow, C. W. Altered proteasomal function in sporadic Parkinson's disease. Exp. Neurol. 179, 38–46 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. McNaught, K. S., Belizaire, R., Jenner, P., Olanow, C. W., Isacson, O. Selective loss of 20S proteasome α-subunits in the substantia nigra pars compacta in Parkinson's disease. Neurosci. Lett. 326, 155–158 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Zhu, J. H., Kulich, S. M., Oury, T. D. & Chu, C. T. Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am. J. Pathol. 161, 2087–2098 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhu, J. H., Guo, F., Shelburne, J., Watkins, S. & Chu, C. T. Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol. 13, 473–481 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992).

    Article  CAS  PubMed  Google Scholar 

  111. Soong, N. W., Hinton, D. R., Cortopassi, G. & Arnheim, N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nature Genet. 2, 318–323 (1992).

    Article  CAS  PubMed  Google Scholar 

  112. Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819–822 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Gu, M. et al. Mitochondrial function, GSH and iron in neurodegeneration and Lewy body diseases. J. Neurol. Sci. 158, 24–29 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Mizuno, Y. et al. Mitochondrial energy crisis in Parkinson's disease. Adv. Neurol. 60, 282–287 (1993).

    CAS  PubMed  Google Scholar 

  115. Squier, T. C. Oxidative stress and protein aggregation during biological aging. Exp. Gerontol. 36, 1539–1550 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Alam, Z. I. et al. A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. J. Neurochem. 69, 1326–1329 (1997).

    Article  CAS  PubMed  Google Scholar 

  117. Alam, Z. I. et al. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J. Neurochem. 69, 1196–1203 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Dexter, D. T. et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J. Neurochem. 52, 381–389 (1989).

    Article  CAS  PubMed  Google Scholar 

  119. Beach, T. G., Walker, R. & McGeer, E. G. Patterns of gliosis in Alzheimer's disease and aging cerebrum. Glia 2, 420–436 (1989).

    Article  CAS  PubMed  Google Scholar 

  120. Damier, P., Hirsch, E. C., Zhang, P., Agid, Y. & Javoy-Agid, F. Glutathione peroxidase, glial cells and Parkinson's disease. Neuroscience 52, 1–6 (1993).

    Article  CAS  PubMed  Google Scholar 

  121. Forno, L. S., DeLanney, L. E., Irwin, I., Di, M. D. & Langston, J. W. Astrocytes and Parkinson's disease. Prog. Brain Res. 94, 429–436 (1992).

    Article  CAS  PubMed  Google Scholar 

  122. Sheffield, L. G. & Berman, N. E. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol. Aging 19, 47–55 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. McGeer, P. L., Itagaki, S. & McGeer, E. G. Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 76, 550–557 (1988).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful for the dedication and effort of all members of our investigative teams and the generous support provided by the US National Institutes of Health (NIH) awards AG10851 and NS58830 (to the Udall Center of Excellence in Parkinson's Disease Research at Michigan State University, USA).

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Author notes

  1. Timothy J. Collier and Nicholas M. Kanaan: T.J.C. and N.M.K. contributed equally to this work.

Authors and Affiliations

  1. Timothy J. Collier and Nicholas M. Kanaan are at the Division of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, Michigan 49503, USA.,

    Timothy J. Collier & Nicholas M. Kanaan

  2. Timothy J. Collier is also at the Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, Michigan 49503, USA.,

    Timothy J. Collier

  3. Jeffrey H. Kordower is at the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.,

    Jeffrey H. Kordower

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  1. Timothy J. Collier
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Correspondence to Timothy J. Collier.

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Competing interests

J.H.K. is a founding scientist with a financial interest in Ceregene Inc., USA.

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Glossary

Lipofuscin

Autofluorescent lipid-containing residues of lysosomal digestion that accumulate in many tissues of the body with advancing age and have been termed 'age pigment'.

Neuromelanin

A modified form of melanin pigment found in dopamine neurons of the substantia nigra.

Probenicid

An adjuvant that, when co-administered with MPTP, blocks rapid clearance of the toxin and its metabolites, producing a progressive rodent model of parkinsonism.

Synucleinopathy

An abnormal structure or quantity of α-synuclein that disrupts the function of cells.

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Collier, T., Kanaan, N. & Kordower, J. Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates. Nat Rev Neurosci 12, 359–366 (2011). https://doi.org/10.1038/nrn3039

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