Protein homeostasis and aging in neurodegeneration

Abstract

Genetic and environmental factors responsible for numerous neurodegenerative diseases vary between disorders, yet age remains a universal risk factor. Age-associated decline in protein homeostasis, or proteostasis, enables disease-linked proteins to adopt aberrant tertiary structures, accumulate as higher-ordered aggregates, and cause a myriad of cellular dysfunctions and neuronal death. However, recent findings suggest that the assembly of disease proteins into tightly ordered aggregates can significantly delay proteotoxic onset. Furthermore, manipulation of metabolic pathways through key signaling components extends lifespan, bolsters proteostasis networks, and delays the onset of proteotoxicity. Thus, understanding the relationship between proteostasis and aging has provided important insights into neurodegeneration.

Protein Folding and Quality Control in the ER

“…Its absence inevitably leads to aberrant folding, degradation defects, and pathological consequences. For instance, the amounts and activities of ER chaperones and foldases decrease with age, resulting in a reduction in basal metabolism, which is responsible for a number of maladies, including neurodegenerative diseases, diabetes, cancer, and obesity (Douglas and Dillin 2010;Naidoo 2009). In addition, there are numerous inherited loss-of-function disorders caused by the mutation of specific genes related to ER homeostasis such as the cystic fibrosis trans-membrane conductance regulator (CFTR) and a 1-antitrypsin Z (ATZ) (Hebert and Molinari 2007).…”

Firefly luciferase mutants as sensors of proteome stress

“…A general imbalance in the activities of the major components of the proteostasis network is suggested to ensue during aging. Adapted from (Douglas and Dillin, 2010). (b) An inverse correlation exists between failure of cellular proteostasis and loss of cellular function during aging.…”

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

“…This protein homeostasis system is comprised of a variety of components, including molecular chaperones, the proteolytic, ubiquitin-proteasome and autophagic degradation pathways, cellular trafficking, and other elements of the cellular stress response (3)(4)(5)(6)(21)(22)(23)(24)(25)(26). The progressive decline of the efficacy of these regulatory processes upon aging is likely to contribute to the increased susceptibility of the elderly population to ageassociated neurodegenerative disorders (3)(4)(5)(6)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Given the intrinsic propensity of proteins to aggregate, it is not surprising that we are endowed with a powerful array of defense mechanisms whose role is to preserve protein homeostasis by helping to maintain proteins in their soluble states and to promote the degradation of those that misfold and aggregate (3)(4)(5)(6)(21)(22)(23)(24)(25). This protein homeostasis system is comprised of a variety of components, including molecular chaperones, the proteolytic, ubiquitin-proteasome and autophagic degradation pathways, cellular trafficking, and other elements of the cellular stress response (3)(4)(5)(6)(21)(22)(23)(24)(25)(26).…”