المؤلفون: Massimiliano Cuccioloni, Matteo Mozzicafreddo, Valentina Cecarini, Mauro Angeletti, Laura Bonfili, Giacomo Rossi, Anna Maria Eleuteri, Jeffrey N. Keller

المصدر: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842:127-134

مصطلحات موضوعية: Proteasome Endopeptidase Complex, Cell Survival, Leupeptins, Proteolysis, Blotting, Western, Cysteine Proteinase Inhibitors, Protein degradation, Cathepsin B, Amyloid beta-Protein Precursor, Ubiquitin, Cell Line, Tumor, Autophagy, medicine, Amyloid precursor protein, Humans, Molecular Biology, biology, medicine.diagnostic_test, Adenine, Immunohistochemistry, Cell biology, Amino Acid Substitution, Proteasome, Biochemistry, Mutation, Ubiquitin–proteasome system, biology.protein, Proteasome inhibitor, Molecular Medicine, Mutant Proteins, medicine.drug

الوصف: 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.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6069901796a75d1be793c0cd8b0c0e80Test
https://doi.org/10.1016/j.bbadis.2013.11.002Test

المؤلفون: Mauro Angeletti, Jeffrey N. Keller, Massimiliano Cuccioloni, Valentina Cecarini, Laura Bonfili, Matteo Mozzicafreddo, Anna Maria Eleuteri

المصدر: Cellular and molecular life sciences : CMLS. 73(18)

مصطلحات موضوعية: 0301 basic medicine, Proteasome Endopeptidase Complex, Cellular homeostasis, Disease, Biology, Protein aggregation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Ubiquitin, Alzheimer Disease, Autophagy, Humans, Molecular Biology, Pharmacology, Neurons, Cell Biology, Cell biology, Crosstalk (biology), 030104 developmental biology, Proteasome, Chaperone (protein), Proteolysis, biology.protein, Molecular Medicine, Microtubule-Associated Proteins, Molecular Chaperones

الوصف: Several integrated proteolytic systems contribute to the maintenance of cellular homeostasis through the continuous removal of misfolded, aggregated or oxidized proteins and damaged organelles. Among these systems, the proteasome and autophagy play the major role in protein quality control, which is a fundamental issue in non-proliferative cells such as neurons. Disturbances in the functionality of these two pathways are frequently observed in neurodegenerative diseases, like Alzheimer’s disease, and reflect the accumulation of protease-resistant, deleterious protein aggregates. In this review, we explored the sophisticated crosstalk between the ubiquitin–proteasome system and autophagy in the removal of the harmful structures that characterize Alzheimer’s disease neurons. We also dissected the role of the numerous shuttle factors and chaperones that, directly or indirectly interacting with ubiquitin and LC3, are used for cargo selection and delivery to one pathway or the other.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1039127cfc6bdf2107040196d7ed22e4Test
https://pubmed.ncbi.nlm.nih.gov/27120560Test