Alpha Synuclein Aggregation in a Neurotoxic Model of Parkinson's Disease
Annual rept. 1 Aug 1999-31 Jul 2000
BOSTON UNIV MA SCHOOL OF MEDICINE
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The cause of Parkinsons disease PD is not known but the pattern of neurodegeneration found in PD can be replicated in some animals species, including primates and mice, by the systemic administration of the neurotoxin 1-methyl-4-phenyl-tetrahydropyridine MPTP MPTP inhibits mitochondrial oxidative phosphorylation and causes oxidative injury leading to cell death. Neurons that degenerate in PD develop characteristic inclusions called Lewy bodies that are composed of aggregates of a synaptic protein, alpha synuclein. The purpose of this study is to determine how MPTP affects cytoskeletal and synaptic proteins and to study the relationship between oxidative damage and the formation of synuclein aggregates within neurons. In the first year of this three-year funding period, we have shown that MPTP treated primates and mice develop synuclein aggregates in neurons that are degenerating in the substantia nigra. Degenerating neurons were identified using tyrosine hydroxylase and dopamine transporter immunocytochemistry. The neurodegenerative process is associated with increased levels of oxidative markers for DNA, protein and lipids as indicated by immunocytochemistry for B-hydroxydeoxyguanosine, 3-nitrotyrosine and malondialdehyde respectively. Over the next 2 years, we plan to study the time course of these changes and precisely define the cytoskeletal and synaptic changes associated with synuclein aggregate formation.
- Anatomy and Physiology
- Medicine and Medical Research