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Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis
A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely ab...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9325807/ https://www.ncbi.nlm.nih.gov/pubmed/34491551 http://dx.doi.org/10.1007/s12311-021-01320-0 |
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author | Kaliszewska, Aleksandra Allison, Joseph Col, Tarik-Tarkan Shaw, Christopher Arias, Natalia |
author_facet | Kaliszewska, Aleksandra Allison, Joseph Col, Tarik-Tarkan Shaw, Christopher Arias, Natalia |
author_sort | Kaliszewska, Aleksandra |
collection | PubMed |
description | A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72, synapses and the cerebellum. Meta-analyses were conducted on studies which reported experimental and control groups with means and standard deviations extracted from figures using the online tool PlotDigitizer. This revealed dendritic defects (P = 0.03), reduced C9orf72 in human patients (P = 0.005) and DPR-related neuronal loss (P = 0.0006) but no neuromuscular junction abnormalities (P = 0.29) or cerebellar neuronal loss (P = 0.23). Our results suggest that dendritic arborisation defects, synaptic gene dysregulation and altered synaptic neurotransmission may drive cerebellar synaptic dysfunction in C9-ALS/FTD. In this review, we discuss how the chronological appearance of the different pathological hallmarks alters synaptic integrity which may have profound implications for disease progression. We conclude that a reduction in C9orf72 protein levels combined with the accumulation of RNA foci and DPRs act synergistically to drive C9 synaptopathy in the cerebellum of C9-ALS/FTD patients. |
format | Online Article Text |
id | pubmed-9325807 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-93258072022-07-28 Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis Kaliszewska, Aleksandra Allison, Joseph Col, Tarik-Tarkan Shaw, Christopher Arias, Natalia Cerebellum Review A hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with synaptic dysfunction identified as an early pathological hallmark. Although TDP-43 pathology and overt neurodegeneration are largely absent from the cerebellum, the pathological hallmarks of RNA foci and dipeptide repeat protein (DPR) inclusions are most abundant. Here, we present a systematic literature search in the databases of PubMed, Scopus, Embase, Web of Science and Science Direct up until March 5, 2021, which yielded 19,515 publications. Following the exclusion criteria, 72 articles were included having referred to C9orf72, synapses and the cerebellum. Meta-analyses were conducted on studies which reported experimental and control groups with means and standard deviations extracted from figures using the online tool PlotDigitizer. This revealed dendritic defects (P = 0.03), reduced C9orf72 in human patients (P = 0.005) and DPR-related neuronal loss (P = 0.0006) but no neuromuscular junction abnormalities (P = 0.29) or cerebellar neuronal loss (P = 0.23). Our results suggest that dendritic arborisation defects, synaptic gene dysregulation and altered synaptic neurotransmission may drive cerebellar synaptic dysfunction in C9-ALS/FTD. In this review, we discuss how the chronological appearance of the different pathological hallmarks alters synaptic integrity which may have profound implications for disease progression. We conclude that a reduction in C9orf72 protein levels combined with the accumulation of RNA foci and DPRs act synergistically to drive C9 synaptopathy in the cerebellum of C9-ALS/FTD patients. Springer US 2021-09-07 2022 /pmc/articles/PMC9325807/ /pubmed/34491551 http://dx.doi.org/10.1007/s12311-021-01320-0 Text en © Crown 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Review Kaliszewska, Aleksandra Allison, Joseph Col, Tarik-Tarkan Shaw, Christopher Arias, Natalia Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title | Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title_full | Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title_fullStr | Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title_full_unstemmed | Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title_short | Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD — a Systematic Review and Meta-Analysis |
title_sort | elucidating the role of cerebellar synaptic dysfunction in c9orf72-als/ftd — a systematic review and meta-analysis |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9325807/ https://www.ncbi.nlm.nih.gov/pubmed/34491551 http://dx.doi.org/10.1007/s12311-021-01320-0 |
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