Molecular and Cellular Mechanisms Affected in ALS

Laura Le Gall; Ekene Anakor; Owen Connolly; Geetha Vijayakumar; William Duddy; Stephanie Duguez

doi:10.3390/jpm10030101

Molecular and Cellular Mechanisms Affected in ALS

Laura Le Gall, Ekene Anakor, Owen Connolly, Geetha Vijayakumar, William Duddy, Stephanie Duguez

Research output: Contribution to journal › Review article › peer-review

119 Citations (Scopus)

271 Downloads (Pure)

Abstract

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

Original language	English
Article number	101
Pages (from-to)	1-34
Number of pages	34
Journal	Journal of Personalized Medicine
Volume	10
Issue number	3
DOIs	https://doi.org/10.3390/jpm10030101
Publication status	Published (in print/issue) - 25 Aug 2020

Bibliographical note

Funding Information:
This work was financed by the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland, Northern Ireland Public Health Agency (HSC R&D) & Ulster University (PI: A Bjourson). LLG was a recipient of the ArSLA PhD fellowship, OC was a recipient of the PhD DELL fellowship, EA was a recipient of the Vice-Chancellor’s Research Scholarships, and UGV was a recipient of the TargetALS fellowship (PI: S Duguez).

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Funding

Funding Information: This work was financed by the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland, Northern Ireland Public Health Agency (HSC R&D) & Ulster University (PI: A Bjourson). LLG was a recipient of the ArSLA PhD fellowship, OC was a recipient of the PhD DELL fellowship, EA was a recipient of the Vice-Chancellor’s Research Scholarships, and UGV was a recipient of the TargetALS fellowship (PI: S Duguez). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

oxidative stress
mitochondria dysfunction
axonal transport
autophagy
endocytosis
secretion
RNA metabolism
MND
excitotoxicity
Oxidative stress
Secretion
Autophagy
Endocytosis
Mitochondria dysfunction
Excitotoxicity
Axonal transport

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/jpm10030101Licence: CC BY

jpm-10-00101Final published version, 3.78 MBLicence: CC BY

Cite this

@article{4581ff37841a4744abe2e7fc8d652dc0,

title = "Molecular and Cellular Mechanisms Affected in ALS",

abstract = "Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only \textasciitilde{}20\% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.",

keywords = "oxidative stress, mitochondria dysfunction, axonal transport, autophagy, endocytosis, secretion, RNA metabolism, MND, excitotoxicity, Oxidative stress, Secretion, Autophagy, Endocytosis, Mitochondria dysfunction, Excitotoxicity, Axonal transport",

author = "\{Le Gall\}, Laura and Ekene Anakor and Owen Connolly and Geetha Vijayakumar and William Duddy and Stephanie Duguez",

note = "Funding Information: This work was financed by the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland, Northern Ireland Public Health Agency (HSC R\&D) \& Ulster University (PI: A Bjourson). LLG was a recipient of the ArSLA PhD fellowship, OC was a recipient of the PhD DELL fellowship, EA was a recipient of the Vice-Chancellor{\textquoteright}s Research Scholarships, and UGV was a recipient of the TargetALS fellowship (PI: S Duguez). Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = aug,

day = "25",

doi = "10.3390/jpm10030101",

language = "English",

volume = "10",

pages = "1--34",

journal = "Journal of Personalized Medicine",

issn = "2075-4426",

publisher = "MDPI",

number = "3",

}

TY - JOUR

T1 - Molecular and Cellular Mechanisms Affected in ALS

AU - Le Gall, Laura

AU - Anakor, Ekene

AU - Connolly, Owen

AU - Vijayakumar, Geetha

AU - Duddy, William

AU - Duguez, Stephanie

N1 - Funding Information: This work was financed by the European Union Regional Development Fund (ERDF) EU Sustainable Competitiveness Programme for N. Ireland, Northern Ireland Public Health Agency (HSC R&D) & Ulster University (PI: A Bjourson). LLG was a recipient of the ArSLA PhD fellowship, OC was a recipient of the PhD DELL fellowship, EA was a recipient of the Vice-Chancellor’s Research Scholarships, and UGV was a recipient of the TargetALS fellowship (PI: S Duguez). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8/25

Y1 - 2020/8/25

N2 - Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

AB - Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

KW - oxidative stress

KW - mitochondria dysfunction

KW - axonal transport

KW - autophagy

KW - endocytosis

KW - secretion

KW - RNA metabolism

KW - MND

KW - excitotoxicity

KW - Oxidative stress

KW - Secretion

KW - Autophagy

KW - Endocytosis

KW - Mitochondria dysfunction

KW - Excitotoxicity

KW - Axonal transport

UR - https://www.mdpi.com/2075-4426/10/3/101

UR - https://www.scopus.com/pages/publications/85089843818

U2 - 10.3390/jpm10030101

DO - 10.3390/jpm10030101

M3 - Review article

C2 - 32854276

SN - 2075-4426

VL - 10

SP - 1

EP - 34

JO - Journal of Personalized Medicine

JF - Journal of Personalized Medicine

IS - 3

M1 - 101

ER -

Molecular and Cellular Mechanisms Affected in ALS

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Neurotoxicity of skeletal muscle extracellular vesicles in Amyotrophic Lateral Sclerosis (ALS): vesicle sub-type specificity, target cell type specificity, and mechanisms of uptake

Secretion of neurotoxic vesicles by muscle cells of ALS patients

Skeletal muscle vesicles as a source of circulating biomarkers in amyotrophic lateral sclerosis

Cite this

Molecular and Cellular Mechanisms Affected in ALS

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Student theses

Neurotoxicity of skeletal muscle extracellular vesicles in Amyotrophic Lateral Sclerosis (ALS): vesicle sub-type specificity, target cell type specificity, and mechanisms of uptake

Secretion of neurotoxic vesicles by muscle cells of ALS patients

Skeletal muscle vesicles as a source of circulating biomarkers in amyotrophic lateral sclerosis

Cite this