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Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia
Christy Hung, Miriam Llorian, Koustav Pal, Frederick J. Livesey, Jyoti Sharma Choudhary, Theodoros I. Roumeliotis, Rickie Patani. Cell Reports, 2025-06-24
Topic: Brain proteins, microglia and lab models
Nucleocytoplasmic transport defects are observed in Alzheimer's disease (AD) and frontotemporal dementia (FTD). Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD. We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally observe the redistribution of mitochondria-related transcripts across AD and FTD neurons. The significantly increased mitochondrial RNA (mtRNA) in the cytosol of AD and FTD mutant neurons raised the possibility of leakage, which motivated us to investigate mtDNA leakage. We reveal abnormal cytoplasmic accumulation of mtDNA in AD and FTD cortical neurons together with evidence of mitochondrial aberrance. Importantly, mislocalisation of nucleic acids, mitochondrial dysfunction and cGAS-STING activation can be ameliorated through VCP D2 ATPase inhibition.
Key findings
- Here, we assess mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those with familial AD or FTD.
- We find that AD- and FTD-causing mutations induce significant changes in mRNA nucleocytoplasmic distribution.
- The significantly increased mitochondrial RNA (mtRNA) in the cytosol of AD and FTD mutant neurons raised the possibility of leakage, which motivated us to investigate mtDNA leakage.
Why it matters
In human iPSC-derived cortical neurons, this study found that mislocalisation of nucleic acids, mitochondrial dysfunction and cGAS-STING activation can be ameliorated through VCP D2 ATPase inhibition. This is a cell model, so it is early and preliminary and does not yet show a treatment for people.
Study details
- Evidence strengthLow
How this study scored 40/100
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 (Cell Reports) |
| Journal's citation record | 3 / 4 | Cell Reports: journal h-index 321 (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 | 4 / 5 | 2025 — within 3 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 | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.2× 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 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Rickie Patani: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40570368) |
| Free to read | 2 / 2 | Free to read |
| Total | 40 / 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. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Hung, C., Llorian, M., Pal, K., Livesey, F. J., Choudhary, J. S., Roumeliotis, T. I., et al. (2025). Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia. Cell Reports. https://doi.org/10.1016/j.celrep.2025.115867
Vancouver
Hung C, Llorian M, Pal K, Livesey FJ, Choudhary JS, Roumeliotis TI, et al. Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia. Cell Reports. 2025. doi:10.1016/j.celrep.2025.115867. PMID: 40570368.
BibTeX
@article{hung2025-40570368,
author = {Hung, Christy and Llorian, Miriam and Pal, Koustav and Livesey, Frederick J. and Choudhary, Jyoti Sharma and Roumeliotis, Theodoros I. and Patani, Rickie},
title = {{Mislocalization of nucleic acids is a convergent and targetable mechanism in Alzheimer's disease and frontotemporal dementia}},
journal = {Cell Reports},
year = {2025},
doi = {10.1016/j.celrep.2025.115867},
pmid = {40570368},
url = {https://doi.org/10.1016/j.celrep.2025.115867}
}
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