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TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models
Monsurat T. Gbadamosi, Giulia Romano, Michela Simbula, Giulia Canarutto, Linda K. Ottoboni, Stefania Paola Corti, Fabian M. Feiguin. International Journal of Molecular Sciences, 2025-11-14
Topic: Brain proteins, microglia and lab models
The pathological loss of nuclear TDP-43 is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leading to extensive alterations in RNA metabolism and a broad number of neuronal transcripts. However, the key effectors linking TDP-43 dysfunction to synaptic defects remain unclear. In this study, using Drosophila and human iPSC-derived motoneurons, we identify Rab4 as a direct and conserved target of TDP-43, whose expression is necessary and sufficient to recover synaptic vesicle recycling, neuromuscular junction growth, and locomotor function in TDP-43-deficient motoneurons. Moreover, Rab4 activity promotes the presynaptic recruitment of futsch/MAP1B, a microtubule-associated protein also regulated by TDP-43, which autonomously supports synaptic growth and vesicle turnover. Together, these findings define a TDP-43/Rab4/futsch/MAP1B regulatory axis that couples endosomal dynamics to cytoskeletal assembly. Furthermore, this functionally coherent module provides a mechanistic basis for understanding how synaptic vulnerability is amplified in disease and offers a framework to identify key compensatory targets capable of sustaining neuronal function in the absence of TDP-43.
Key findings
- Together, these findings define a TDP-43/Rab4/futsch/MAP1B regulatory axis that couples endosomal dynamics to cytoskeletal assembly.
Why it matters
Using Drosophila and human iPSC-derived motoneurons, this study identified Rab4 as a target of TDP-43 whose expression recovered synaptic vesicle recycling and locomotor function in TDP-43-deficient motoneurons. These findings define a regulatory axis and offer a framework to identify compensatory targets, but they are from model systems and not yet treatments.
Study details
- Evidence strengthLow
How this study scored 38/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (International Journal of Molecular Sciences) |
| Journal's citation record | 3 / 4 | International Journal of Molecular Sciences: journal h-index 426 (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 | Laboratory or animal study (title names “drosophila”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Fabian M. Feiguin: h-index 26 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Milan: institution h-index 1,023 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41303511) |
| Free to read | 2 / 2 | Free to read |
| Total | 38 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.3390/ijms262211030
- PubMed: 41303511
- Original source →
- Free full text: International Journal of Molecular Sciences →
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
Gbadamosi, M. T., Romano, G., Simbula, M., Canarutto, G., Ottoboni, L. K., Corti, S. P., et al. (2025). TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms262211030
Vancouver
Gbadamosi MT, Romano G, Simbula M, Canarutto G, Ottoboni LK, Corti SP, et al. TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models. International Journal of Molecular Sciences. 2025. doi:10.3390/ijms262211030. PMID: 41303511.
BibTeX
@article{gbadamosi2025-41303511,
author = {Gbadamosi, Monsurat T. and Romano, Giulia and Simbula, Michela and Canarutto, Giulia and Ottoboni, Linda K. and Corti, Stefania Paola and Feiguin, Fabian M.},
title = {{TDP-43 Regulates Rab4 Levels to Support Synaptic Vesicle Recycling and Neuromuscular Connectivity in Drosophila and Human ALS Models}},
journal = {International Journal of Molecular Sciences},
year = {2025},
doi = {10.3390/ijms262211030},
pmid = {41303511},
url = {https://doi.org/10.3390/ijms262211030}
}
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