Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer's disease

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

Cecarini, Valentina¹  Bonfili, Laura¹  Cuccioloni, Massimiliano¹  Mozzicafreddo, Matteo¹  Rossi, Giacomo²  Buizza, Laura³  Uberti, Daniela³  Angeletti, Mauro¹  Eleuteri, Anna Maria¹ 

[1] Univ Camerino, Sch Biosci & Biotechnol, I-62032 Camerino, Italy

[2] Univ Camerino, Sch Med Vet Sci, I-62024 Matelica, Italy

[3] Univ Brescia, Dept Biomed Sci & Biotechnol, I-25123 Brescia, Italy

关键词: Proteasome;    Autophagy;    Amyloid;    Alzheimer's disease;    HDAC6;   

DOI  :  10.1016/j.bbadis.2012.07.015

来源: Elsevier

【 摘 要 】

Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-beta precursor protein (A beta PP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type A beta PP gene or 717 valine-to-glycine A beta PP-mutated gene. The over-expression of the A beta PP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-beta(42) oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an A beta(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional. (C) 2012 Elsevier B.V. All rights reserved.

【 授权许可】

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