%0 Journal Article
%T The Role of Alpha-Synuclein Oligomerization and Aggregation in Cellular and Animal Models of Parkinson¡¯s Disease
%A Oi Wan Wan
%A Kenny K. K. Chung
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0038545
%X ¦Á-synuclein (¦Á-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 ¦Á-syn contributes to LB formation and PD is still not well-understood. It has been proposed that aggregation of ¦Á-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 ¦Á-syn oligomers. In this study, we have generated ¦Á-syn mutants that have increased propensity to form aggregates by attaching a CL1 peptide to the C-terminal of ¦Á-syn. Data from our cellular study suggest an inverse correlation between cell viability and the amount of ¦Á-syn aggregates formed in the cells. In addition, our animal model of PD indicates that attachment of CL1 to ¦Á-syn enhanced its toxicity to dopaminergic neurons in an age-dependent manner and induced the formation of Lewy body-like ¦Á-syn aggregates in the substantia nigra. These results provide new insights into how ¦Á-syn-induced toxicity is related to its aggregation.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0038545