TY - JOUR
T1 - Endoplasmic reticulum proteostasis impairment in aging
AU - Martínez, Gabriela
AU - Duran-Aniotz, Claudia
AU - Cabral-Miranda, Felipe
AU - Vivar, Juan P.
AU - Hetz, Claudio
N1 - Funding Information:
This work was directly funded by FONDAP program 15150012, US Office of Naval Research-Global (ONR-G) N62909-16-1-2003, Millennium Institute P09-015-F, FONDEF ID16I10223, FONDEF D11E1007, U.S. Air Force Office of Scientific Research FA9550-16-1-0384, CONICYT-Brazil 441921/2016-7, FONDECYT no 11160760 (CDA), and FONDECYT no 3150637 (GM). We also thank the support from ALS Therapy Alliance 2014-F-059, Muscular Dystrophy Association 382453, Michael J Fox Foundation for Parkinson's Research—Target Validation grant No 9277, FONDECYT no. 1140549, and ALSRP Therapeutic Idea Award AL150111 (CH).
Publisher Copyright:
© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2017/8
Y1 - 2017/8
N2 - Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.
AB - Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.
KW - aging
KW - endoplasmic reticulum
KW - endoplasmic reticulum stress
KW - protein misfolding disorders
KW - unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85018635685&partnerID=8YFLogxK
U2 - 10.1111/acel.12599
DO - 10.1111/acel.12599
M3 - Review article
C2 - 28436203
AN - SCOPUS:85018635685
SN - 1474-9718
VL - 16
SP - 615
EP - 623
JO - Aging Cell
JF - Aging Cell
IS - 4
ER -