Cargando…

Autophagy and ALS: mechanistic insights and therapeutic implications

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 p...

Descripción completa

Detalles Bibliográficos
Autores principales: Chua, Jason P., De Calbiac, Hortense, Kabashi, Edor, Barmada, Sami J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942428/
https://www.ncbi.nlm.nih.gov/pubmed/34057020
http://dx.doi.org/10.1080/15548627.2021.1926656
_version_ 1784673304065343488
author Chua, Jason P.
De Calbiac, Hortense
Kabashi, Edor
Barmada, Sami J.
author_facet Chua, Jason P.
De Calbiac, Hortense
Kabashi, Edor
Barmada, Sami J.
author_sort Chua, Jason P.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8942428
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-89424282022-03-24 Autophagy and ALS: mechanistic insights and therapeutic implications Chua, Jason P. De Calbiac, Hortense Kabashi, Edor Barmada, Sami J. Autophagy Review 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. Taylor & Francis 2021-05-31 /pmc/articles/PMC8942428/ /pubmed/34057020 http://dx.doi.org/10.1080/15548627.2021.1926656 Text en © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Review
Chua, Jason P.
De Calbiac, Hortense
Kabashi, Edor
Barmada, Sami J.
Autophagy and ALS: mechanistic insights and therapeutic implications
title Autophagy and ALS: mechanistic insights and therapeutic implications
title_full Autophagy and ALS: mechanistic insights and therapeutic implications
title_fullStr Autophagy and ALS: mechanistic insights and therapeutic implications
title_full_unstemmed Autophagy and ALS: mechanistic insights and therapeutic implications
title_short Autophagy and ALS: mechanistic insights and therapeutic implications
title_sort autophagy and als: mechanistic insights and therapeutic implications
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8942428/
https://www.ncbi.nlm.nih.gov/pubmed/34057020
http://dx.doi.org/10.1080/15548627.2021.1926656
work_keys_str_mv AT chuajasonp autophagyandalsmechanisticinsightsandtherapeuticimplications
AT decalbiachortense autophagyandalsmechanisticinsightsandtherapeuticimplications
AT kabashiedor autophagyandalsmechanisticinsightsandtherapeuticimplications
AT barmadasamij autophagyandalsmechanisticinsightsandtherapeuticimplications