Wild type and mutant amyloid precursor proteins influence downstream effects of proteasome and autophagy inhibition

• Published in: Biochimica et biophysica acta 2014-02, Vol.1842 (2), p.127-134
• Main Authors: Cecarini, Valentina, Bonfili, Laura, Cuccioloni, Massimiliano, Mozzicafreddo, Matteo, Rossi, Giacomo, Keller, Jeffrey N., Angeletti, Mauro, Eleuteri, Anna Maria
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Amino Acid Substitution; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Autophagy; Autophagy - drug effects; Autophagy - physiology; Blotting, Western; Cathepsin B; Cathepsin B - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Cysteine Proteinase Inhibitors - pharmacology; Humans; Immunohistochemistry; Leupeptins - pharmacology; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Proteasome Endopeptidase Complex - metabolism; Proteolysis - drug effects; Ubiquitin–proteasome system
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.11.002

Cells rely on complementary proteolytic pathways including the ubiquitin–proteasome system and autophagy to maintain proper protein degradation. There is known to be considerable interplay between them, whereby the loss of one clearance system results in compensatory changes in other proteolytic pathways of the cell. Disturbances in proteolysis are known to occur in Alzheimer's disease, and potentially contribute to neurophysiological and neurodegenerative processes. Currently, few data are available on how the presence of wild type and mutant amyloid precursor protein (APPwt and APPmut) potentially alters the reciprocal interplay between the different intracellular proteolytic pathways. This study used human SH-SY5Y neuronal cell lines, and SH-SY5Y transfected with either APPwt or APPmut (valine-to-glycine substitution at position 717), in order to explore if the presence of APPwt or APPmut altered the downstream effects of pharmacological proteasome or autophagy inhibition. The occurrence of APPwt or APPmut was observed to disturb proteasome or autophagy activities upon treatment with proteasome inhibitors or authophagy inhibitors. Interestingly, APPwt and APPmut expression was observed to significantly and robustly enhance the induction in cathepsin B following the administration of an established proteasome inhibitor. The presence of APPwt and APPmut also significantly reduced the elevation in ubiquitinated proteins following proteasome inhibitor treatments. Our data strongly suggest that APP is able to affect the downstream effects of protease inhibition in neural cells including enhancement of cathepsin B activity, with these changes in cathepsin B significantly and inversely related to the levels of ubiquitinated protein. •The UPS and autophagy are strictly and bidirectionally interdependent.•APPwt or APPmut disturbs proteasome or autophagy activities upon exposure to specific inhibitors.•APPwt and APPmut expression enhances the induction in cathepsin B after administration of MG132.•APPwt and APPmut reduces the elevation in ubiquitinated proteins upon MG132 exposure.