The sequential processing of the APP (amyloid precursor protein) by the β- and γ-secretase and generation of the Aβ (amyloid-β) peptide is a primary pathological factor in AD (Alzheimer's disease). Regulation of the processing or turnover of these proteins represents potential targets for the development of AD therapies. Sumoylation is a process by which SUMOs (small ubiquitin-like modifiers) are covalently conjugated to target proteins, resulting in a number of functional consequences. These include regulation of protein–protein interactions, intracellular trafficking and protein stability, which all have the potential to impact on several aspects of the amyloidogenic pathway. The present study examines the effects of overexpression and knockdown of the major SUMO isoforms (SUMO1, 2 and 3) on APP processing and the production of Aβ peptides. SUMO3 overexpression significantly increased Aβ40 and Aβ42 secretion, which was accompanied by an increase in full-length APP and its C-terminal fragments. These effects of SUMO3 were independent of its covalent attachment or chain formation, as mutants lacking the motifs responsible for SUMO chain formation or SUMO conjugation led to similar changes in Aβ. SUMO3 overexpression also up-regulated the expression of the transmembrane protease BACE (β-amyloid-cleaving enzyme), but failed to affect levels of several other unrelated proteins. Suppression of SUMO1 or combined SUMO2+3 by RNA interference did not affect APP levels or Aβ production. These findings confirm a specific effect of SUMO3 overexpression on APP processing and the production of Aβ peptides but also suggest that endogenous sumoylation is not essential and likely plays an indirect role in modulating the amyloid processing pathway.
Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins
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Véronique Dorval, Matthew J. Mazzella, Paul M. Mathews, Ronald T. Hay, Paul E. Fraser; Modulation of Aβ generation by small ubiquitin-like modifiers does not require conjugation to target proteins. Biochem J 1 June 2007; 404 (2): 309–316. doi: https://doi.org/10.1042/BJ20061451
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