Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.

Abemaciclib and Vacuolin-1 decrease aggregate-prone TDP-43 accumulation by accelerating autophagic flux

“…In patients with ALS and FTLD-TDP, disease-causing gene mutations have been shown to suppress autophagy via a number of pathways [ 2 , 26 ]. Autosomal dominant ALS-linked profilin 1 mutants formed aggregates that co-localized with LC3 and decreased the level of the autophagosome marker LC3-II [ 10 ].…”

Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches

“…In ALS, motor neuron survival is directly affected by an impairment in the autophagic pathway. More specifically, axonal transport defects are suggested to be responsible for the autophagosome accumulation observed in ALS mice ( Cozzi and Ferrari, 2022 ). Autophagy is known to be dysregulated in ALS at different steps of the pathway, which results in autophagosome accumulation and a defective autophagic flux ( Song et al, 2012 ; Lee et al, 2015 ; Nguyen et al, 2019 ).…”

Biochemical and Molecular Pathways in Neurodegenerative Diseases: An Integrated View

“…The autophagy gene BECN1 , encoding the mammalian orthologue of the yeast Atg6 (Beclin-1), has reduced messenger RNA (mRNA) levels in AD brain tissue [ 157 ]. Further, mutations in the ALS-causing gene DCTN1 lead to impaired dynein/dynactin motor protein function, causing defects in the transport of autophagosomes, inducing axonopathy [ 158 ], and hence, motor neuron degeneration [ 159 , 160 , 161 ]. Moreover, the depletion of dynein/dynactin motor protein leads to neuromuscular synapse instability and functional abnormalities in both sporadic (sALS) and fALS [ 160 , 162 , 163 ] ( Figure 3 ).…”