Home › Research › Lewy body dementia
The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity
Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, Jiang S, Ma X et al.. Nature medicine, 2016-06-27
Topic: Brain proteins, microglia and lab models
Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Wang, W., Wang, L., Lu, J., Siedlak, S. L., Fujioka, H., Liang, J., et al. (2016). The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature medicine. https://doi.org/10.1038/nm.4130
Vancouver
Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nature medicine. 2016. doi:10.1038/nm.4130. PMID: 27348499.
BibTeX
@article{wang2016-27348499,
author = {Wang, W. and Wang, L. and Lu, J. and Siedlak, S. L. and Fujioka, H. and Liang, J. and Jiang, S. and Ma, X. and others},
title = {{The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity}},
journal = {Nature medicine},
year = {2016},
doi = {10.1038/nm.4130},
pmid = {27348499},
url = {https://doi.org/10.1038/nm.4130}
}
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD).
- Disease-associated mutations increase TDP-43 mitochondrial localization.
- In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly.
- The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice.
- Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.
Why it matters
In neurons from people with ALS or frontotemporal dementia, TDP-43 accumulated in mitochondria and impaired respiratory complex I, and blocking this mitochondrial localization improved phenotypes in mutant TDP-43 mice. This is laboratory and animal work proposing a possible therapeutic target, not a proven treatment for patients.
Study details
- Evidence strengthLow
How this study scored 58/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (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 | 1 / 5 | 2016 — within 20 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 460 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 38.3 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 5 / 6 | Cited 23.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 12 other studies in this library |
| Still being cited | 3 / 4 | Cited 147 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Xinglong Wang: h-index 65 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Massachusetts General Hospital: institution h-index 2,057 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 27348499) |
| Free to read | 2 / 2 | Free to read |
| Total | 58 / 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).
Related
Studies in the library that share something with this one. The line above each title says what.
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 14.
Later studies that cite this one
12 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Lewy body dementia
Also tagged “tdp-43”
1,150 studies in the library carry the topic tag “tdp-43”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.