Cargando…
Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton change...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203826/ https://www.ncbi.nlm.nih.gov/pubmed/34140881 http://dx.doi.org/10.3389/fncel.2021.660693 |
_version_ | 1783708251369504768 |
---|---|
author | Nishimura, Agnes L. Arias, Natalia |
author_facet | Nishimura, Agnes L. Arias, Natalia |
author_sort | Nishimura, Agnes L. |
collection | PubMed |
description | Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton changes. Synergies between loss of C9orf72 functions and gain of function by toxic effects of repeat expansions also contribute to C9orf72-mediated pathogenesis. However, the impact of haploinsufficiency of C9orf72 on neurons and in synaptic functions requires further examination. As the motor neurons degenerate, the disease symptoms will lead to neurotransmission deficiencies in the brain, spinal cord, and neuromuscular junction. Altered neuronal excitability, synaptic morphological changes, and C9orf72 protein and DPR localization at the synapses, suggest a potential involvement of C9orf72 at synapses. In this review article, we provide a conceptual framework for assessing the putative involvement of C9orf72 as a synaptopathy, and we explore the underlying and common disease mechanisms with other neurodegenerative diseases. Finally, we reflect on the major challenges of understanding C9orf72-ALS as a synaptopathy focusing on integrating mitochondrial and neuronal cytoskeleton degeneration as biomarkers and potential targets to treat ALS neurodegeneration. |
format | Online Article Text |
id | pubmed-8203826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82038262021-06-16 Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion Nishimura, Agnes L. Arias, Natalia Front Cell Neurosci Cellular Neuroscience Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton changes. Synergies between loss of C9orf72 functions and gain of function by toxic effects of repeat expansions also contribute to C9orf72-mediated pathogenesis. However, the impact of haploinsufficiency of C9orf72 on neurons and in synaptic functions requires further examination. As the motor neurons degenerate, the disease symptoms will lead to neurotransmission deficiencies in the brain, spinal cord, and neuromuscular junction. Altered neuronal excitability, synaptic morphological changes, and C9orf72 protein and DPR localization at the synapses, suggest a potential involvement of C9orf72 at synapses. In this review article, we provide a conceptual framework for assessing the putative involvement of C9orf72 as a synaptopathy, and we explore the underlying and common disease mechanisms with other neurodegenerative diseases. Finally, we reflect on the major challenges of understanding C9orf72-ALS as a synaptopathy focusing on integrating mitochondrial and neuronal cytoskeleton degeneration as biomarkers and potential targets to treat ALS neurodegeneration. Frontiers Media S.A. 2021-06-01 /pmc/articles/PMC8203826/ /pubmed/34140881 http://dx.doi.org/10.3389/fncel.2021.660693 Text en Copyright © 2021 Nishimura and Arias. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular Neuroscience Nishimura, Agnes L. Arias, Natalia Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title | Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title_full | Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title_fullStr | Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title_full_unstemmed | Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title_short | Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion |
title_sort | synaptopathy mechanisms in als caused by c9orf72 repeat expansion |
topic | Cellular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203826/ https://www.ncbi.nlm.nih.gov/pubmed/34140881 http://dx.doi.org/10.3389/fncel.2021.660693 |
work_keys_str_mv | AT nishimuraagnesl synaptopathymechanismsinalscausedbyc9orf72repeatexpansion AT ariasnatalia synaptopathymechanismsinalscausedbyc9orf72repeatexpansion |