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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...

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Autores principales: Kaliszewska, Aleksandra, Allison, Joseph, Col, Tarik-Tarkan, Shaw, Christopher, Arias, Natalia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2021
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.
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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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