Endoplasmic reticulum proteostasis impairment in aging

• Published in: Aging cell Vol. 16; no. 4; pp. 615 - 623
• Main Authors: Martínez, Gabriela, Duran‐Aniotz, Claudia, Cabral‐Miranda, Felipe, Vivar, Juan P., Hetz, Claudio
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.08.2017; John Wiley and Sons Inc
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Aging; Aging - drug effects; Aging - metabolism; Aging - pathology; Animals; Brain - drug effects; Brain - metabolism; Brain - pathology; Caenorhabditis elegans - drug effects; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans - metabolism; Cell death; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila melanogaster - metabolism; Endoplasmic reticulum; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Guanabenz - pharmacology; Homeostasis; Humans; Indoles - pharmacology; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - prevention & control; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurophysiology; Protective Agents - pharmacology; Protein biosynthesis; Protein folding; protein misfolding disorders; Protein transport; Proteins; Proteome - genetics; Proteome - metabolism; Proteomes; Proteostasis - drug effects; Proteostasis Deficiencies - metabolism; Proteostasis Deficiencies - pathology; Proteostasis Deficiencies - prevention & control; Review; Reviews; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Secretion; Therapeutic applications; unfolded protein response; Unfolded Protein Response - drug effects; unfolded protein response; protein misfolding disorders; aging; endoplasmic reticulum; endoplasmic reticulum stress
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12599

Summary 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.