The role of alpha-synuclein oligomerization and aggregation in cellular and animal models of Parkinson's disease.
α-Synuclein (α-syn) is a synaptic protein in which four mutations (A53T, A30P, E46K and gene triplication) have been found to cause an autosomal dominant form of Parkinson's disease (PD). It is also the major component of intraneuronal protein aggregates, designated as Lewy bodies (LBs), a prominent pathological hallmark of PD. How α-syn contributes to LB formation and PD is still not well-understood. It has been proposed that aggregation of α-syn contributes to the formation of LBs, which then leads to neurodegeneration in PD. However, studies have also suggested that aggregates formation is a protective mechanism against more toxic α-syn oligomers. In this study, we have generated α-syn mutants that have increased propensity to form aggregates by attaching a CL1 peptide to the C-terminal of α-syn. Data from our cellular study suggest an inverse correlation between cell viability and the amount of α-syn aggregates formed in the cells. In addition, our animal model of PD indicates that attachment of CL1 to α-syn enhanced its toxicity to dopaminergic neurons in an age-dependent manner and induced the formation of Lewy body-like α-syn aggregates in the substantia nigra. These results provide new insights into how α-syn-induced toxicity is related to its aggregation.
Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong, China.
Oi Wan
OW
Wan
Kenny K K
KK
Chung
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D002850:Chromatography, Gel; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D016631:Lewy Bodies / Q000235:genetics*; D051379:Mice; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D010455:Peptides / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D058105:Polymerization; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
D010455:Peptides; D051844:alpha-Synuclein