Pasniceanu, I.-S., Atwal, M.S., Souza, C.D.S. et al. (2 more authors) (2021) Emerging mechanisms underpinning neurophysiological impairments in C9ORF72 repeat expansion-mediated amyotrophic lateral sclerosis/frontotemporal dementia. Frontiers in Cellular Neuroscience, 15. 784833. ISSN 1662-5102
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Pasniceanu, Atwal, Souza, Ferraiuolo and Livesey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). 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. |
Keywords: | C9ORF72; neuron; synaptic; excitability; glutamate; physiology; ALS (amyotrophic lateral sclerosis); FTD (frontotemporal dementia) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number ASTRAZENECA PLC nan ASTRAZENECA UK LIMITED 10047321 ROYAL SOCIETY RGS\R1\211173 MOTOR NEURONE DISEASE ASSOCIATION Livesey/Oct20/900-792 ROSETREES TRUST Seedcorn2020\100144 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Jan 2022 12:58 |
Last Modified: | 06 Jan 2022 12:58 |
Status: | Published |
Publisher: | Frontiers Media |
Refereed: | Yes |
Identification Number: | 10.3389/fncel.2021.784833 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182160 |