Data di Pubblicazione:
2023
Citazione:
STUB1 mutants effect on TBP behavior in digenic spinocerebellar ataxia type 17 / P. Pramaggiore, M. Stefania, M. Chierichetti, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, M. Piccolella, V. Crippa, M. Galbiati, B. Daniela Di, T. Franco, A. Poletti, R.M. Cristofani. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 166:S1(2023 Aug), pp. B04-11.103-B04-11.103. (Intervento presentato al convegno ISN-ESN MEETING tenutosi a Porto : 8-11 August nel 2023).
Abstract:
Spinocerebellar ataxias (SCAs) are hereditary, progressive, heterogenous neurodegenerative diseases (NDs). SCA type 17 (SCA17) presents an expansion of CAG nucleotide repeats of the TATA-box binding (TBP) gene that codes for an abnormally long polyglutamine (polyQ) tract in the N-terminal. This leads to reduced solubility and accumulation of the mutant TBP in neurons. Strikingly, TBP forms containing an intermediate polyQ tract (41-47/49 Qs) show incomplete penetrance (SCA17-DI). Mutations in STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP), an E3 ubiquitin-ligase which participates in the protein quality control (PQC) system, plays a crucial role in SCA17-DI. Since TBP and STUB1 may be both involved in SCA17-DI we investigated their behaviour and interplay to better understand the underlying molecular mechanisms in disease.
Our data show a punctate distribution and insoluble protein accumulation of elongated polyQ TBP, not observed in the wild-type or intermediate polyQ TBP expressing neurons. TBP accumulation is reverted by STUB1 over-expression suggesting that TBP degradation is mediated by STUB1. Since STUB1 plays a role in both ubiquitin proteasome system (UPS) and autophagy, we alternatively inhibited these pathways to study TBP behaviour. Autophagy inhibition did not modify STUB1 activity on TBP-Qs protein levels and aggregation. UPS inhibition blocked STUB1-mediated degradation on TBP-WT and TBP-Q54, while it did not affect TBP-Q43 protein levels suggesting that different pathways are responsible for STUB1-mediated TBP-Qs removal. Moreover, STUB1 SCA17-DI-linked mutations showed reduced activity on TBP clearance.
Our data demonstrate that STUB1 mutations affect TBP biochemical behaviour in SCA17-DI. Therefore, we want to further investigate TBP and STUB1 interplay to better understand their pathological role.
GRANTS: Fondazione Cariplo (2021-1544); National Center for Gene Therapy and Drugs based on RNA Technology (CN_00000041); Fondazione Regionale per la Ricerca Biomedica (FRRB_grant_Care4NeuroRare CP_20/2018 to F.T.).
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
P. Pramaggiore, M. Stefania, M. Chierichetti, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, M. Piccolella, V. Crippa, M. Galbiati, B. Daniela Di, T. Franco, A. Poletti, R.M. Cristofani
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