Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities

Abstract

Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

“…A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti‐aging cellular mechanism (Chang, Kumsta, Hellman, Adams & Hansen, 2017; Cuervo, 2008; Garcia‐Prat et al., 2016; Madeo, Zimmermann, Maiuri & Kroemer, 2015; Rubinsztein, Marino & Kroemer, 2011). Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age‐related diseases (Hara et al., 1997; Komatsu et al., 2006, 2007; Menzies et al., 2017). Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles (Kaushik & Cuervo, 2015; Kennedy et al., 2014; Lopez‐Otin, Blasco, Partridge, Serrano & Kroemer, 2013).…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…In terms of mTOR‐independent mechanisms for autophagy restoration, activation of AMPK (AMP‐activated protein kinase) usually becomes the optimal pharmaceutical solution, such as the use of trehalose and metformin (Menzies, Fleming, Caricasole, Bento, & Andrews, 2017). Trehalose, a disaccharide that inhibits glucose transporters, leads to the activation of AMPK and autophagy, attenuating the proteotoxic effects in affected neurons (DeBosch, Heitmeier, Mayer, Higgins, & Crowley, 2016; Menzies et al., 2017).…”

“…Trehalose, a disaccharide that inhibits glucose transporters, leads to the activation of AMPK and autophagy, attenuating the proteotoxic effects in affected neurons (DeBosch, Heitmeier, Mayer, Higgins, & Crowley, 2016; Menzies et al., 2017). Metformin, another well‐known AMPK activator initially approved to treat patients with diabetes, could also restore the machinery of autophagy and exhibit anti‐AD effects (Levy et al., 2017).…”

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…Mechanistically, the cellular components (misfolded proteins (aggrephagy), overloaded peroxisomes (pexophagy), pathogenic organisms (xenophagy) and dysfunctional mitochondria (mitophagy)) are engulfed by autophagosomes which then move towards and fuse with lysosomes and are then degraded [53]. A complicated series of signaling cascades and autophagy-related proteins (ATG) contribute to the completion of autophagy [50].…”

“…Evidence is presented suggesting amyloid oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, additional cofactors are required [13]. Those cofactors include several subcellular processes including oxidative damage [10,[14][15][16][17][18][19][20][21][22][23], recruitment of peripheral immune cells and excessive production of pro-inflammatory mediators [10,[24][25][26][27][28][29], mitochondrial impairments and chronic energy imbalance [12,20,[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47], chronic endoplasmic reticulum (ER) stress [48] and autophagy dysfunction [22,[49][50][51][52][53][54], the abnormality and dysfunction of MAM (the mitocho...…”