A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation -: Implications for pathogenesis of Parkinson disease

Parkinson disease and other alpha-synucleinopathies are characterized by the deposition of intraneuronal alpha-synuclein (alpha Syn) inclusions. A significant fraction (about 15%) of alpha Syn in these pathological structures are truncated forms that have a much higher propensity than the full-length alpha Syn to form aggregates in vitro. However, little is known about the role of truncated alpha Syn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated alpha Syns induce rapid aggregation of full- length protein at sub-stoichiometric ratios. Co-overexpression of truncated alpha Syn with full- length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated alpha Syn in the pathogenesis of diseases involving alpha Syn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble alpha Syns that correlates with the onset of pathology in transgenic mice expressing human alpha Syn-A53T mutant. The caspase-like activity of the 20 S proteasome produces truncated fragments similar to those found in patients and animal models from degradation of unstructured alpha Syn. We propose a model in which incomplete degradation of alpha Syn, especially under overloaded proteasome capacity, produces highly amyloidogenic fragments that rapidly induce the aggregation of full- length protein. These aggregates in turn reduce proteasome activity, leading to further accumulation of fragmented and full- length alpha Syns, creating a vicious cycle of cytotoxicity. This model has parallels in other neurodegenerative diseases, such as Huntington disease, where coaggregation of poly(Q) fragments with full- length protein has been observed.