The Role of Alpha-Synuclein Oligomerization and Aggregation in Cellular and Animal Models of Parkinson's Disease

alpha-synuclein (alpha-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 alpha-syn contributes to LB formation and PD is still not well-understood. It has been proposed that aggregation of alpha-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 alpha-syn oligomers. In this study, we have generated alpha-syn mutants that have increased propensity to form aggregates by attaching a CL1 peptide to the C-terminal of alpha-syn. Data from our cellular study suggest an inverse correlation between cell viability and the amount of alpha-syn aggregates formed in the cells. In addition, our animal model of PD indicates that attachment of CL1 to alpha-syn enhanced its toxicity to dopaminergic neurons in an age-dependent manner and induced the formation of Lewy body-like alpha-syn aggregates in the substantia nigra. These results provide new insights into how alpha-syn-induced toxicity is related to its aggregation.