Raquel S Lima1, Daniel C Carrettiero2, Merari F R Ferrari3. 1. Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Rua do Matao, 277, Cidade Universitaria, Sao Paulo, SP, 05508-090, Brazil. 2. Centro de Ciencias Naturais e Humanas, Universidade Federal do ABC, Santo Andre, SP, Brazil. 3. Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Rua do Matao, 277, Cidade Universitaria, Sao Paulo, SP, 05508-090, Brazil. merari@usp.br.
Abstract
BACKGROUND: Protein aggregates are pathological hallmarks of many neurodegenerative diseases, however the physiopathological role of these aggregates is not fully understood. Protein quality control has a pivotal role for protein homeostasis and depends on specific chaperones. The co-chaperone BAG2 can target phosphorylated Tau for degradation by an ubiquitin-independent pathway, although its possible role in autophagy was not yet elucidated. In view of this, the aim of the present study was to investigate the association among protein aggregation, autophagy and BAG2 levels in cultured cells from hippocampus and locus coeruleus as well as in SH-SY5Y cell line upon different protein aggregation scenarios induced by rotenone, which is a flavonoid used as pesticide and triggers neurodegeneration. METHODS AND RESULTS: The present study showed that rotenone exposure at 0.3 nM for 48 h impaired autophagy prior to Tau phosphorylation at Ser199/202 in hippocampus but not in locus coeruleus cells, suggesting that distinct neuron cells respond differently to rotenone toxicity. Rotenone induced Tau phosphorylation at Ser199/202, together with a decrease in the endogenous BAG2 protein levels in SH-SY5Y and hippocampus cell culture, which indicates that rotenone and Tau hyperphosphorylation can affect this co-chaperone. Finally, it has been shown that BAG2 overexpression, increased p62/SQSTM1 levels in cells from hippocampus and locus coeruleus, stimulated LC3II recycling as well as prevented the raise of phosphorylated Tau at Ser199/202 in hippocampus. CONCLUSIONS: Results demonstrate a possible role for BAG2 in degradation pathways of specific substrates and its importance for the study of cellular aspects of neurodegenerative diseases.
BACKGROUND: Protein aggregates are pathological hallmarks of many neurodegenerative diseases, however the physiopathological role of these aggregates is not fully understood. Protein quality control has a pivotal role for protein homeostasis and depends on specific chaperones. The co-chaperone BAG2 can target phosphorylated Tau for degradation by an ubiquitin-independent pathway, although its possible role in autophagy was not yet elucidated. In view of this, the aim of the present study was to investigate the association among protein aggregation, autophagy and BAG2 levels in cultured cells from hippocampus and locus coeruleus as well as in SH-SY5Y cell line upon different protein aggregation scenarios induced by rotenone, which is a flavonoid used as pesticide and triggers neurodegeneration. METHODS AND RESULTS: The present study showed that rotenone exposure at 0.3 nM for 48 h impaired autophagy prior to Tau phosphorylation at Ser199/202 in hippocampus but not in locus coeruleus cells, suggesting that distinct neuron cells respond differently to rotenone toxicity. Rotenone induced Tau phosphorylation at Ser199/202, together with a decrease in the endogenous BAG2 protein levels in SH-SY5Y and hippocampus cell culture, which indicates that rotenone and Tau hyperphosphorylation can affect this co-chaperone. Finally, it has been shown that BAG2 overexpression, increased p62/SQSTM1 levels in cells from hippocampus and locus coeruleus, stimulated LC3II recycling as well as prevented the raise of phosphorylated Tau at Ser199/202 in hippocampus. CONCLUSIONS: Results demonstrate a possible role for BAG2 in degradation pathways of specific substrates and its importance for the study of cellular aspects of neurodegenerative diseases.
Authors: Y Yamamura; S Kuzuhara; K Kondo; T Yanagi; M Uchida; H Matsumine; Y Mizuno Journal: Parkinsonism Relat Disord Date: 1998-08 Impact factor: 4.891
Authors: Yahyah Aman; Tomas Schmauck-Medina; Malene Hansen; Richard I Morimoto; Anna Katharina Simon; Ivana Bjedov; Konstantinos Palikaras; Anne Simonsen; Terje Johansen; Nektarios Tavernarakis; David C Rubinsztein; Linda Partridge; Guido Kroemer; John Labbadia; Evandro F Fang Journal: Nat Aging Date: 2021-08-12