Implications of Selective Autophagy Dysfunction for ALS Pathology

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

“…They also provided evidence that p62 can directly bind to a mutated form of SOD1, suggesting that p62 can target mutant SOD1 to selective autophagy in an ubiquitin-dependent mechanism. Autophagy impairment or p62 loss of function may therefore contribute in ALS pathogenesis [ 122 ]. Moreover, functional p62, through stimulation of Nrf2- mediated antioxidant response, also serves a protective function against oxidative stress related with SOD1 mutations [ 123 ].…”

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

“…Importantly, over 20 fALS-associated genes have been identified, where these genes are broadly associated with proteostasis mechanisms including protein degradation, protein production (RNA metabolism), and protein trafficking (Taylor et al, 2016 ; Yerbury et al, 2020 ). Comprehensive reviews of the genetics and resulting pathomechanisms of ALS have been reviewed elsewhere (Matus et al, 2013 ; Renton et al, 2014 ; Carrì et al, 2015 ; Medinas et al, 2017b ; Nguyen et al, 2018 ; Burk and Pasterkamp, 2019 ; Mejzini et al, 2019 ; Vicencio et al, 2020 ).…”

Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease, Lithium, and Autophagy

“…It is noteworthy that manifestation of different neurodegenerative diseases such as AD [ 88 , 89 ], ALS [ 90 , 91 ], Parkinson’s [ 92 , 93 ], and Huntington’s disease [ 94 , 95 , 96 ] share similar pathogenesis characteristics including neuroinflammation, mitochondrial dysfunction, enhanced apoptosis and attenuated autophagy—all positively affected by lithium. Indeed, studies of the potential beneficial effect of lithium in neurodegenerative disorders, tested at the cellular, animal models and patients levels are cumulating.…”