Molecular pathogenesis of Parkinson disease.

Parkinson disease (PD), the most common neurodegenerative movement disorder, is characterized by an extensive and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. One of the pathological hallmarks of PD is the presence of Lewy bodies, intracellular inclusions of aggregated alpha-synuclein. Although the cause and pathogenesis of selective loss of dopamine neurons and the accumulation of alpha-synuclein in PD remain elusive, growing lines of evidence from environmental risk factors and early-onset genetics point to a convergence between energy metabolism and the disposal of damaged proteins in the development of PD. These findings suggest that impairments in mitochondrial and ubiquitin-proteasome system function can significantly contribute to the pathogenesis of PD. This review will summarize recent insights gained from genetic and environmental studies of PD that underscore this association.

[1]  J. C. Greene,et al.  Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[2]  T. Dawson,et al.  Parkin-associated Parkinson’s disease , 2004, Cell and Tissue Research.

[3]  M. Cookson,et al.  Mitochondria and Dopamine New Insights into Recessive Parkinsonism , 2004, Neuron.

[4]  D. Perl,et al.  Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease , 2004, Annals of neurology.

[5]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[6]  Janel O. Johnson,et al.  α-Synuclein Locus Triplication Causes Parkinson's Disease , 2003, Science.

[7]  P. Lockhart,et al.  Parkin Protects against the Toxicity Associated with Mutant α-Synuclein Proteasome Dysfunction Selectively Affects Catecholaminergic Neurons , 2002, Neuron.

[8]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[9]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[10]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[11]  L. Petrucelli,et al.  Caught in the Act α-Synuclein Is the Culprit in Parkinson's Disease , 2003, Neuron.

[12]  T. Dawson,et al.  Rare genetic mutations shed light on the pathogenesis of Parkinson disease. , 2003, The Journal of clinical investigation.

[13]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.