Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Feb;18(2):254-282.
doi: 10.1080/15548627.2021.1926656. Epub 2021 May 31.

Autophagy and ALS: mechanistic insights and therapeutic implications

Jason P Chua  1 , Hortense De Calbiac  2 , Edor Kabashi  2 , Sami J Barmada  1
Affiliations
Review

Autophagy and ALS: mechanistic insights and therapeutic implications

Jason P Chua et al. Autophagy. 2022 Feb.

Abstract

Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.Abbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.

Keywords: Amyotrophic lateral sclerosis; C9orf72; CHMP2B; SQSTM1/p62; TBK1; macroautophagy; mitophagy; myelinophagy; neuronal autophagy; optineurin.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Dysfunction of autophagy-related proteins impairs proteostasis and leads to neurotoxicity in ALS. (A) Under normal conditions, SQSTM1 serves as a receptor protein in selective autophagy and binds both LC3-II and polyubiquitinated proteins, thereby targeting ubiquitinated substrates to phagophores (left); Mutations in SQSTM1 abrogate SQSTM1’s binding activities (right top) or result in the aggregation of SQSTM1 into ubiquitin-positive inclusions (right bottom). (B) The C9orf72 protein participates in several autophagy-related complexes, including the autophagy induction complex (ULK1-RAB1A) that promotes autophagosome biogenesis, the RAB7-RAB11 complex (RAB complex) that regulates endosome maturation, and the C9orf72-SMCR8-WDR41 (CSW) complex that regulates lysosomal dynamics and autophagic flux (left). Disease-associated C9orf72 mutations reduce C9orf72 protein levels (right), while dipeptide repeat proteins generated from the C9orf72 expansion localize to SQSTM1- and ubiquitin-positive inclusions (right). (C) In normal mitophagy, TBK1 binds and phosphorylates OPTN, enhancing its affinity for polyubiquitinated mitochondria and LC3-II (left). TBK1 and OPTN mutations perturb these functions and compromise efficient mitophagy, leading to failed mitochondrial clearance and dysfunctional mitochondria.
Figure 2.
Figure 2.
Distinct factors regulate autophagy among different cell types of the nervous system. In each of the cells which comprise the central and peripheral nervous systems, autophagy is differentially regulated by cell type-specific effectors. In neurons (top left), modulation of SPHK1 by phenoxazine compounds such as 10-NCP, but not starvation, potently induces autophagy. In contrast, nutrient deprivation is sufficient to promote SPHK1 signaling and autophagy induction in astrocytes (top center). In the axonal compartment of neurons, KIF1A and PINK1-PRKN are critical for facilitating local autophagic activity (left, middle). MicroRNAs such as MIR101 and MIR195 suppress oligodendrocytic and Schwann cell autophagy, respectively (right). Schwann cells also clear myelin debris through myelinophagy, a unique form of selective autophagy that is dependent on FIG4 (bottom). In muscle, specific transcription factors can exert activating (FOXO3) or suppressive (PPARGC1A, RUNX1) effects on autophagy, and phosphatases such as MTM1 and MTMR14 inhibit autophagy by recycling phosphoinositides needed for autophagy induction (bottom left).
Figure 3.
Figure 3.
Mechanisms of neuronal autophagy and their impact for therapeutic design in ALS. Pharmacodynamic considerations limit the use of currently available drugs for modulating autophagy. Inhibitors of MTOR inhibitors (rapalogs) only weakly activate autophagy in neurons, and their wide-ranging effects target myriad cellular pathways, including growth signaling, translation, stress responses, transcriptional regulation, and cytoskeletal remodeling (left). Such pleiotropy leads to well-documented and multi-systemic toxicities, especially with long-term use; however, newer rapalogs may enable more specific targeting and selective autophagy modulation. Similarly, lithium has numerous multi-target effects, including depletion of IP3 through IMPase, activating nitric oxide synthase, inhibiting GSK3B, stimulating NMDA receptors and enhancing glutamatergic tone, among many others (middle). This results in a narrow therapeutic index for lithium, potentially explaining its apparent lack of neuroprotective effects in human trials for neurodegenerative disease to date. To reduce off-target effects, recent efforts have focused on MTOR-independent strategies for stimulating autophagy, including modulation of SIRT1, phenoxazine compounds such as 10-NCP, or synthetic peptides such as Tat-Beclin 1 (right).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. De Duve C, Wattiaux R.. Functions of lysosomes. Annu Rev Physiol. 1966;28(1):435–492. - PubMed
    1. Klionsky DJ. Autophagy revisited: a conversation with Christian de Duve. Autophagy. 2008;4(6):740–743. - PubMed
    1. Fimia GM, Stoykova A, Romagnoli A, et al. Ambra1 regulates autophagy and development of the nervous system. Nature. 2007;447(7148):1121–1125. DOI:10.1038/nature05925. - DOI - PubMed
    1. Gan B, Peng X, Nagy T, et al. Role of FIP200 in cardiac and liver development and its regulation of TNFalpha and TSC-mTOR signaling pathways. J Cell Biol. 2006;175(1):121–133. DOI:10.1083/jcb.200604129. - DOI - PMC - PubMed
    1. Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–1036. DOI:10.1038/nature03029. - DOI - PubMed

Publication types