A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies
Marrero-Gagliardi, A.; Noda, J.; Zanovello, M.; Gerenu, G.; Armas, J. M. B.; Bampton, A.; Torres, P.; Hernandez-Eguiazu, H.; Moragon, S.; Pellegrini, F.; Perez, C.; Fumagallo, F.; Taoro, L.; Alfaro, R. A. M. d. B.; Brown, A. L.; Quinet, G.; Andres-Benito, P.; Ferrer, I.; Acebes, A.; Freire, R.; Smits, V. A. J.; Keuss, M.; Portero-Otin, M.; Lashley, T.; Fratta, P.; Acevedo-Arozena, A.; Gil-Bea, F.
Show abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterised by the progressive degeneration of specific neurons, that are defined by the appearance of TDP-43 pathology leading to TDP-43 cytoplasmic aggregation coupled with its nuclear loss. Although the causes of TDP-43 pathology in TDP-43 proteinopathies remain unclear, stress response may play a significant role, with some TDP-43 co-localizing with stress granules (SG). The ubiquitin-specific protease 10 (USP10) is a critical inhibitor of SG assembly. Here, we identify a new functional interaction between TDP-43 and USP10, with both proteins modulating different key aspects of the biology of the other. Adding to their functional connection, we assign a new function to USP10 as a modulator of alternative splicing, sharing a subset of splicing targets with TDP-43. Critically, we found that USP10 levels can increase in postmortem tissue from ALS and FTD patients and that USP10 can ameliorate TDP-43 mediated toxicity in vivo in an animal model, overall suggesting a new role for USP10 in TDP-43 proteinopathies.
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