A Precipitation Role for Truncated α-Synuclein and the Proteasome in α-Synuclein Aggregation.

Parkinson disease and other ɑ-synucleinopathies are characterized by the deposition of intraneuronal ɑ-synuclein (ɑSyn) inclusions. A significant fraction (about 15%) of ɑSyn in these pathological structures are truncated forms that have a much higher propensity than the full-length ɑSyn to form aggregates in vitro. However, little is known about the role of truncated ɑSyn species in pathogenesis or the means by which they are generated. Here, we have provided an in vitro mechanistic study demonstrating that truncated ɑSyns induce rapid aggregation of full-length protein at substoichiometric ratios. Co-overexpression of truncated ɑSyn with full-length protein increases cell vulnerability to oxidative stress in dopaminergic SH-SY5Y cells. These results suggest a precipitating role for truncated ɑSyn in the pathogenesis of diseases involving ɑSyn aggregation. In this regard, the A53T mutation found in some cases of familial Parkinson disease exacerbates the accumulation of insoluble ɑSyns that correlates with the onset of pathology in transgenic mice expressing human ɑSyn-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 ɑSyn. We propose a model in which incomplete degradation of ɑSyn, 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 ɑSyns, 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. [ABSTRACT FROM AUTHOR]