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Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis
Kaliszewska A, Allison J, Col TT, Shaw C, Arias N.. Cerebellum (London, England), 2021-09-07
Topic: Brain proteins, microglia and lab models
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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APA 7th
Kaliszewska, A., Allison, J., Col, T. T., Shaw, C., & Arias, N. (2022). Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis. Cerebellum (London, England). https://doi.org/10.1007/s12311-021-01320-0
Vancouver
Kaliszewska A, Allison J, Col TT, Shaw C, Arias N. Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis. Cerebellum (London, England). 2022. doi:10.1007/s12311-021-01320-0. PMID: 34491551.
BibTeX
@article{kaliszewska2022-34491551,
author = {Kaliszewska, A. and Allison, J. and Col, T. T. and Shaw, C. and Arias, N.},
title = {{Elucidating the Role of Cerebellar Synaptic Dysfunction in C9orf72-ALS/FTD - a Systematic Review and Meta-Analysis}},
journal = {Cerebellum (London, England)},
year = {2022},
doi = {10.1007/s12311-021-01320-0},
pmid = {34491551},
url = {https://doi.org/10.1007/s12311-021-01320-0}
}
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Key findings
- 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.
- 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.
Why it matters
Reviewing 72 articles on the C9orf72 gene, the most common genetic cause of ALS and frontotemporal dementia, researchers looked at synapse damage in the cerebellum. Meta-analysis showed defects in nerve-cell branches (dendrites), reduced C9orf72 in patients and neuron loss tied to toxic repeat proteins, but no overall cerebellar neuron loss. The authors conclude that lower C9orf72 protein combined with RNA foci and repeat proteins act together to damage synapses, which concerns frontotemporal dementia rather than Alzheimer's.
Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 50/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cerebellum (London, England)) |
| Journal's citation record | 1 / 4 | The Cerebellum: journal h-index 107 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| Times cited | 2 / 7 | Cited 14 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.3 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 1 / 6 | Cited 0.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 10 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Natalia Arias: h-index 16 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | King's College London: institution h-index 1,348 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34491551) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
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