α-Synuclein and the Parkinson's disease-related mutant Ala53Thr-α-synuclein do not undergo proteasomal degradation in HEK293 and neuronal cells

Synucleins are neuronal proteins detectable in the neuropathological lesions of several cerebral disorders. Thus, alpha-synuclein immunoreactivity is found in Lewy bodies, the histopathological hallmark of sporadic Parkinson disease-affected brains. When mutated, alpha-synuclein seems to be responsible for some familial forms of Parkinson disease. As Lewy bodies are enriched in ubiquitinated structures and also contain proteasome-related immunoreactivity, it could be hypothesized that the proteasome contributes to the cellular degradation of alpha-synucleins, thereby controlling their concentration-dependent aggregation process. Here, we first demonstrate that alpha-synuclein is not ubiquitinated in HEK293 cells. Furthermore, by means of two specific inhibitors, we show that wild type and Ala53Thr alpha-synuclein do not behave as proteasome substrates in HEK293 cells a nd mu ri ne neurons. Our study indicates that the proteasome does not contribute to the control of cellular synucleins concentration and therefore, unlikely participates to cerebral alpha-synucleinopathies. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.