Augmenting brain metabolism to increase macro- and chaperone-mediated autophagy for decreasing neuronal proteotoxicity and aging. (September 2017)

• Record Type: Journal Article
• Authors: Loos, Ben; Klionsky, Daniel J.; Wong, Esther
• Is Part Of: Progress in neurobiology. Volume 156(2017:Sep.)
• Page Start: 90
• Page End: 106
• Publication Date: 2017-09
• Subjects: AD Alzheimer disease -- ATP adenosine triphosphate -- AMP adenosine monophosphate -- AMPK AMP-activated protein kinase -- BDNF brain derived neurotrophic factor -- CMA chaperone-mediated autophagy -- CR caloric restriction -- Ex exercise -- GABA gamma-aminobutyric acid -- HSP70 heat shock protein 70 -- HD huntington disease -- HDAC6 histone deacetylase 6 -- KD ketogenic diet -- LGIT low glycaemic index treatment -- MAD modified Atkins diet -- MCT medium-chain triglyceride -- MTORC1 mechanistic target of rapamycin complex 1 -- MTORC2 mechanistic target of rapamycin complex 2 -- PD Parkinson disease -- PKA protein kinase A -- UPS ubiquitin-proteasome system -- UPDRS Unified Parkinson Disease Rating Scale -- TCA tricarboxylic acid -- T2D Type 2 diabetes; Autophagic flux -- Caloric restriction -- Exercise -- Ketone bodies -- Longevity -- Neurodegeneration; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2017.05.001
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging, with dysfunctions in both macroautophagy and CMA contributing to proteo- and neuro-toxicity associated with neurodegeneration and aging. This review highlights critically, to what extent life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise may enhance both autophagy and brain health. The functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration is being mapped out. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. Novel insights are provided for a potential adjuvant therapeutic strategy to intervene in the neuronal decline by controlling both macroautophagy and CMA fluxes favorably. Abstract: Accumulation of toxic protein aggregates in the nerve cells is a hallmark of neuronal diseases and brain aging. Mechanisms to enhance neuronal surveillance to improve neuronal proteostasis have a direct impact on promoting neuronal health and forestalling age-related decline in brain function. Autophagy is a lysosomal degradative pathway pivotal for neuronal protein quality control. Different types of autophagic mechanisms participate in protein handling in neurons. Macroautophagy targets misfolded and aggregated proteins in autophagic vesicles to the lysosomes for destruction, while chaperone-mediated autophagy (CMA) degrades specific soluble cytosolic proteins delivered to the lysosomes by chaperones. Dysfunctions in macroautophagy and CMA contribute to proteo- and neuro-toxicity associated with neurodegeneration and aging. Thus, augmenting or preserving both autophagic mechanisms pose significant benefits in delaying physiological and pathological neuronal demises. Recently, life-style interventions that modulate metabolite ketone bodies, energy intake by caloric restriction and energy expenditure by exercise have shown to enhance both autophagy and brain health. However, to what extent these interventions affect neuronal autophagy to promote brain fitness remains largely unclear. Here, we review the functional connections of how macroautophagy and CMA are affected by ketone bodies, caloric restriction and exercise in the context of neurodegeneration. A concomitant assessment of yeast Saccharomyces cerevisiae is performed to reveal the conserved nature of such autophagic responses to substrate perturbations. In doing so, we provide novel insights and integrated evidence for a potential adjuvant therapeutic strategy to intervene in the neuronal decline in neurodegenerative diseases by controlling both macroautophagy and CMA fluxes favorably.