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Review
. 2022 Jul;72(7):1456-1481.
doi: 10.1007/s12031-022-02029-3. Epub 2022 Jun 16.

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Marta Cozzi  1 , Veronica Ferrari  2
Affiliations
Review

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Marta Cozzi et al. J Mol Neurosci. 2022 Jul.

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.

Keywords: Amyotrophic lateral sclerosis; Animal models; Autophagy; Mutations.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic representation of the ALS-related gene products involved in autophagy initiation (green) in their conventional intracellular functions
Fig. 2
Fig. 2
Schematic representation of the ALS-related gene products involved in autophagosome elongation and maturation (green) in their conventional intracellular functions
Fig. 3
Fig. 3
Schematic representation of the ALS-related gene products involved in autophagosome-lysosome fusion and degradation (green) in their conventional intracellular functions
Fig. 4
Fig. 4
Schematic representation of the ALS-related gene products involved in endocytosis (green) in their conventional intracellular functions
See this image and copyright information in PMC

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