Home › Research › Lewy body dementia
Molecular mechanisms underlying nucleotide repeat expansion disorders
Malik I, Kelley CP, Wang ET, Todd PK.. Nature reviews. Molecular cell biology, 2021-06-17
Topic: Brain proteins, microglia and lab models
The human genome contains over one million short tandem repeats. Expansion of a subset of these repeat tracts underlies over fifty human disorders, including common genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72), polyglutamine-associated ataxias and Huntington disease, myotonic dystrophy, and intellectual disability disorders such as Fragile X syndrome. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.
Key findings
- In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides.
- Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features.
- We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis.
- We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated.
- Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.
Why it matters
This review describes four major ways that expanded short tandem repeats cause disease, including in ALS and frontotemporal dementia, and suggests that these mechanisms may offer therapeutic targets. It does not test any treatment or prevention for Alzheimer's disease, so it has no direct implications for treating, curing, or preventing the disease.
Study details
- Evidence strengthLow
How this study scored 53/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Nature reviews. Molecular cell biology) |
| Journal's citation record | 4 / 4 | Nature Reviews Molecular Cell Biology: journal h-index 622 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 367 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 52.4 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 4 / 6 | Cited 8.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 4 / 4 | Cited 237 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Peter K. Todd: h-index 40 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Michigan: institution h-index 2,240 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34140671) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021). Molecular mechanisms underlying nucleotide repeat expansion disorders. Nature reviews. Molecular cell biology. https://doi.org/10.1038/s41580-021-00382-6
Vancouver
Malik I, Kelley CP, Wang ET, Todd PK. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nature reviews. Molecular cell biology. 2021. doi:10.1038/s41580-021-00382-6. PMID: 34140671.
BibTeX
@article{malik2021-34140671,
author = {Malik, I. and Kelley, C. P. and Wang, E. T. and Todd, P. K.},
title = {{Molecular mechanisms underlying nucleotide repeat expansion disorders}},
journal = {Nature reviews. Molecular cell biology},
year = {2021},
doi = {10.1038/s41580-021-00382-6},
pmid = {34140671},
url = {https://doi.org/10.1038/s41580-021-00382-6}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 18.
Later studies that cite this one
2 studies in the alzhub library list this one in their references.
Related studies in Lewy body dementia
Also tagged “bodies”
1,017 studies in the library carry the topic tag “bodies”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,017 tagged studies.