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Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra.
Acta Neuropathol. 2006 Aug; 112(2):115-26.AN

Abstract

Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD.

Authors+Show Affiliations

Departments of Neurology, Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, USA. galvinj@neuro.wustl.edu

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

16791599

Citation

Galvin, James E.. "Interaction of Alpha-synuclein and Dopamine Metabolites in the Pathogenesis of Parkinson's Disease: a Case for the Selective Vulnerability of the Substantia Nigra." Acta Neuropathologica, vol. 112, no. 2, 2006, pp. 115-26.
Galvin JE. Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra. Acta Neuropathol. 2006;112(2):115-26.
Galvin, J. E. (2006). Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra. Acta Neuropathologica, 112(2), 115-26.
Galvin JE. Interaction of Alpha-synuclein and Dopamine Metabolites in the Pathogenesis of Parkinson's Disease: a Case for the Selective Vulnerability of the Substantia Nigra. Acta Neuropathol. 2006;112(2):115-26. PubMed PMID: 16791599.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra. A1 - Galvin,James E, Y1 - 2006/06/22/ PY - 2006/04/28/received PY - 2006/06/05/accepted PY - 2006/06/05/revised PY - 2006/6/23/pubmed PY - 2007/2/3/medline PY - 2006/6/23/entrez SP - 115 EP - 26 JF - Acta neuropathologica JO - Acta Neuropathol VL - 112 IS - 2 N2 - Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD. SN - 0001-6322 UR - https://www.unboundmedicine.com/medline/citation/16791599/Interaction_of_alpha_synuclein_and_dopamine_metabolites_in_the_pathogenesis_of_Parkinson's_disease:_a_case_for_the_selective_vulnerability_of_the_substantia_nigra_ L2 - https://dx.doi.org/10.1007/s00401-006-0096-2 DB - PRIME DP - Unbound Medicine ER -