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Mechanism of α-synuclein cleavage by the 20S proteasome. Inhibition of α-synuclein degradation by oxidation of its N-terminal methionines and reversion by methionine sulforeductase A

AuthorsÁlvarez-Castelao, Beatriz; Goethals, Marc; Vandekerckhove, Joël; Castaño, José G.
Issue Date2011
CitationXXXIV Congreso SEBBM (2011)
Abstractα-Synuclein is implicated in the pathophysiology of Parkinson’s disease (PD) and is found aggregated in intracytoplasmic inclusions. α-Synuclein is degraded directly by the 20S proteasome. We have found that α-Synuclein interacts with the C-terminal portion of C8 subunit of the proteasome trough its N-terminal region (aa1-60). The released peptides after proteasomal digestion were separated by RP-HPLC and analyzed by MALDI-TOF MS/MS, from these data we can conclude that initial cleavages of α-synuclein occur within the N-terminal region of the α-synuclein molecule. Aggregated α-synucleins wild type and its missense mutants (A30P, E46K and A53T) showed a reduced rate of degradation by the proteasome when compared with native α-synucleins. This inhibition was likely due to Met oxidation of the monomeric α-synuclein still present in the aggregated α-synuclein preparations. These results suggest that oxidation of native α-synuclein should result in the inhibition of its degradation by the proteasome. In fact, oxidation of α-synuclein with H2O2 produced the inhibition of its degradation by the 20S proteasome. The inhibition was mainly due to oxidation of Met 1 and 5 at the N-terminal region of α-synuclein and could be reversed by treatment of oxidized α-synuclein with methionine sulforeductase A. In conclusion, the Met RedOx control of α-synuclein cleavage by the proteasome illustrates that protein oxidation does not necessarily mean facilitated degradation by the proteasome, and open a new way to understand proteostasis in the cell under physiological, including aging, and pathological conditions allowing further understanding of the pathology of PD and other synucleinopathies.
DescriptionResumen del trabajo presentado al XXXIV Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Barcelona del 5 al 8 de septiembre de 2011.
Appears in Collections:(IIBM) Comunicaciones congresos
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