Alpha-synuclein and the Parkinson's disease-related mutant Ala53Thr-alpha-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 and murine 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.
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Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UPR411, 660 Route des Lucioles, Sophia Antipolis, 06560, Valbonne, France.
Alves da Costa
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Uéda
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Checler
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D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D051843:Synucleins; D013912:Threonine / Q000235:genetics; D014162:Transfection; D051844:alpha-Synuclein
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D013912:Threonine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000409:Alanine