Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress - PubMed
3 days ago
- #TDP-43
- #ER stress
- #ALS
- TDP-43 aggregation is linked to ALS and FTLD-TDP pathologies.
- USP19 is identified as a deubiquitinase that removes ubiquitin conjugates from TDP-43, promoting its cytoplasmic aggregation.
- The ER-anchored USP19 isoform (USP19-ER) is more effective in deubiquitinating TDP-43 C-terminal fragments (TDP-CTFs) than the cytosolic isoform (USP19-Cyto).
- USP19 couples TDP-CTF aggregation to ER stress pathways (ATF6, ATF4, IRE1, & CHOP).
- Increased USP19 levels in FTLD-TDP brains correlate with cytoplasmic phospho-TDP-43 pathology.
- Genetic reduction of usp19 in mice mitigates TDP-43 pathology, ER stress, and improves LTP and motor deficits.
- USP19 plays a critical role in TDP-43 proteostasis and ER stress, implicating its pathogenic role in FTLD-TDP and ALS.