Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

Abstract

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

Mitophagy Modulation, a New Player in the Race against ALS

“…Several molecules are able to reduce TDP-43 aggregates by means of autophagy stimulation, some examples are rapamycin or trehalose. However, the effects of autophagy modulators rely heavily upon the ALS model used [ 70 ]. Verapamil has been shown to delay the onset of the disease, increase life expectancy, regain the functionality of affected motor neurons, and reduce the aggregation of SOD1 by increasing autophagy in the SOD1 G93A model [ 71 ].…”

“…Autophagic stimulation of clemastine shows beneficial effects only in the short term, and presents no effect on survival or disease progression in the long term [ 74 ]. Rapamycin shows null or negative effects on SOD1 models, but beneficial effects in a TDP-43 model [ 70 ]. This issue is more raveled with respect to trehalose, where contradictory data can be found.…”

“…Time-lapse studies have shown that the temporal dynamics of neuronal mitophagy are very slow, in which lysosomal fusion and acidification are the rate-limiting stages [ 80 ]. Indeed, several ALS-related mutations in genes such as C9orf72 , ALS2 , or CHMPB2 are involved in autophagosome maturation defects and their fusion with the lysosomes [ 70 ]. All of this defines a hypothetical model where mitophagy induction may be detrimental at late stages of neurodegeneration due to an accumulation of nonfunctional vacuolated organelles and the inability of the neuron to provide new healthy mitochondria ( Figure 3 ).…”

Mitophagy Regulates Neurodegenerative Diseases

“…On the other hand, as noted in PD, AD, and HD, the accumulation of neurotoxic misfolded proteins and aggregates within motor neurons is a primary pathological hallmark of ALS [151]. SOD1 and TDP-43-associated aggregation are the vital protein aggregates in ALS patients.…”

Molecular Basis of Neuronal Autophagy in Ageing: Insights from Caenorhabditis elegans

“…Oxidative stress, DNA damage, telomere shortening and inflammation play prominent causative role in ageing [ 130 , 131 , 132 , 133 ]. These factors can compromise cellular proteostatic mechanisms such as autophagy and contribute to the development or progression of age-related neurodegenerative disorders, such as Alzheimer’s, Huntington’s or Parkinson’s disease, and amyotrophic lateral sclerosis [ 134 , 135 , 136 , 137 , 138 ].…”