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Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration
Melamed Z, López-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, Freyermuth F, McMahon MA et al.. Nature neuroscience, 2019-01-14
Topic: Brain proteins, microglia and lab models
Plain-language summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43). Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS-FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.
What this study adds
Evidence grade: Low
In ALS and frontotemporal dementia, the protein TDP-43 is lost from the cell nucleus, and this study found that without it neurons make a cut-short, non-working copy of the message for stathmin-2, a protein tied to nerve growth. Reduced stathmin-2 turned up in motor neurons from people with sporadic ALS and with C9orf72-linked ALS.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Melamed, Z., López-Erauskin, J., Baughn, M. W., Zhang, O., Drenner, K., Sun, Y., et al. (2019). Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nature neuroscience. https://doi.org/10.1038/s41593-018-0293-z
Vancouver
Melamed Z, López-Erauskin J, Baughn MW, Zhang O, Drenner K, Sun Y, et al. Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration. Nature neuroscience. 2019. doi:10.1038/s41593-018-0293-z. PMID: 30643298.
BibTeX
@article{melamed2019-30643298,
author = {Melamed, Z. and López-Erauskin, J. and Baughn, M. W. and Zhang, O. and Drenner, K. and Sun, Y. and Freyermuth, F. and McMahon, M. A. and others},
title = {{Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration}},
journal = {Nature neuroscience},
year = {2019},
doi = {10.1038/s41593-018-0293-z},
pmid = {30643298},
url = {https://doi.org/10.1038/s41593-018-0293-z}
}
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
- Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear transactive response DNA-binding protein 43 (TDP-43).
Why it matters
In ALS and frontotemporal dementia, the protein TDP-43 is lost from the cell nucleus, and this study found that without it neurons make a cut-short, non-working copy of the message for stathmin-2, a protein tied to nerve growth. Reduced stathmin-2 turned up in motor neurons from people with sporadic ALS and with C9orf72-linked ALS. In lab-grown motor neurons, restoring stathmin-2 brought back the ability of nerve fibres to regrow; the authors call the loss "a hallmark of ALS-FTD", but this rescue was shown only in cells in a dish, not in patients.
Study details
- Evidence strengthLow
How this study scored 62/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Nature neuroscience) |
| Journal's citation record | 4 / 4 | Nature Neuroscience: journal h-index 593 (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 | 2 / 5 | 2019 — within 10 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 634 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 70.4 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 5 / 6 | Cited 30.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 26 other studies in this library |
| Still being cited | 4 / 4 | Cited 330 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Don W. Cleveland: h-index 165 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30643298) |
| Free to read | 2 / 2 | Free to read |
| Total | 62 / 100 | — |
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