Endolysosomal dysfunction impairs proteostasis and induces neurodegeneration in vivo
Transactive response (TAR) DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. Dysfunction of the endolysosomal system, which plays a crucial role in protein trafficking and maintaining proteostasis, has been implicated in FTD-ALS pathogenesis. While the impact of endolysosomal dysfunction on TDP-43 pathology remains unclear, we demonstrated that disrupting the endolysosomal pathway by expressing the constitutively active endosomal protein, Rab5<sup>Q79L</sup>, induces TDP-43 aggregation in cultured cells. Here, we generated a mouse model expressing GFP-tagged Rab5<sup>Q79L</sup>, demonstrating that GFP-Rab5<sup>Q79L</sup> mice exhibit early motor deficits and endolysosomal dysfunction, including enlarged endosomes, abnormal lysosome morphology, and p62- or ubiquitin-positive inclusions. These mice also developed significant neuronal loss, neuroinflammation, phosphorylated TDP-43 (pTDP-43) inclusions, and nuclear envelope and nuclear pore structural defects reminiscent of FTD-ALS. Accordingly, GFP-Rab5<sup>Q79L</sup> mice will prove useful in expanding our understanding of endolysosomal dysfunction in proteostasis and pTDP-43 pathology.
Authors
- Monica Castanedes‐Casey (ORCID: https://orcid.org/0000-0002-8441-7801)
- Dennis W. Dickson (ORCID: https://orcid.org/0000-0001-7189-7917)
- Mercedes Prudencio (ORCID: https://orcid.org/0000-0002-4894-4858)
- Karen Jansen‐West (ORCID: https://orcid.org/0000-0002-1234-7103)
- Judith A. Dunmore (ORCID: https://orcid.org/0000-0003-0190-0089)
- Lillian M. Daughrity (ORCID: https://orcid.org/0000-0003-4644-7265)
- Casey Cook (ORCID: https://orcid.org/0000-0002-5963-8442)
- Desiree Zanetti Alepuz (ORCID: https://orcid.org/0009-0009-0825-6899)
- Leonard Petrucelli (ORCID: https://orcid.org/0000-0003-2959-129X)
- Tiffany W. Todd (ORCID: https://orcid.org/0000-0003-4327-6114)
- Jimei Tong
- Peizhou Jiang (ORCID: https://orcid.org/0000-0002-3761-3068)
- Yari Carlomagno (ORCID: https://orcid.org/0000-0001-5530-7737)
- Tania F. Gendron (ORCID: https://orcid.org/0000-0002-7335-2627)
- Paula Castellanos Otero
- Ellen A. Albagli
- Emma Lee (ORCID: https://orcid.org/0000-0001-7033-6632)
- Wei Shao (ORCID: https://orcid.org/0000-0002-8554-7245)
- Aishe Kurti
- Yong-Jie Zhang
- Mei Yue
- Anxhela Hysi
Institutions
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- iScience
- Published
- 2025-08-27
- DOI
- https://doi.org/10.1016/j.isci.2025.113460
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- BrightFocus Foundation
- Mayo Foundation for Medical Education and Research
- Target ALS
- National Institutes of Health
- Robert Packard Center for ALS Research, Johns Hopkins University