Spinocerebellar ataxias (SCAs) are hereditary, progressive and fatal, very heterogenous neurodegenerative diseases (NDs). SCA type 17 (SCA17) is characterized by the presence of expanded CAG nucleotide repeats of the TATA-box binding (TBP) gene that codes for an abnormally long polyglutamine (polyQ) tract in the N- terminal of the protein. This leads to reduced solubility and accumulation of mutated TBP in neurons. Strikingly, TBP forms containing an intermediate polyQ tract (41-47 Qs) show incomplete penetrance (SCA17- DI), which seems to be correlated to the presence of mutations in STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP). STUB1 is an E3 ubiquitin-ligase which has a key role in the protein quality control (PQC) system. Given the hypothesis that both TBP and STUB1 may be involved in SCA17-DI, we investigated their behaviour and interplay for a deeper understanding of the underlying molecular mechanisms in the disease. Our data show a punctate distribution and insoluble protein accumulation of overexpressed elongated polyQ TBP (TBP-Q54) that it is not present in the wild type (TBP-WT) or intermediate polyQ TBP (TBP-Q43) expressing neurons. Interestingly, 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. Our preliminary findings suggest that different pathways are responsible for STUB1-mediated TBP-Qs removal based on the different sizes of the polyQ tract. Moreover, other analyses show that STUB1 SCA17-DI-linked mutations are characterized by a reduced activity on TBP clearance. Collectively, our data demonstrate that STUB1 mutations affect TBP biochemical behaviour in SCA17-DI. Therefore, our goal is to further investigate TBP and STUB1 interplay in order to better understand their pathological role in this form of ataxia, leading to a deeper knowledge of the disease. GRANTS: Fondazione Cariplo (2021-1544)

STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP) mutants as a key factor on TATA-box binding protein (TBP) behaviour in digenic spinocerebellar ataxia type 17 (SCA17-DI) / P. Pramaggiore, S. Magri, M. Chierichetti, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, V. Crippa, M. Galbiati, L. Cornaggia, G. Patelli, D. Di Bella, F. Taroni, A. Poletti, R. Cristofani. ((Intervento presentato al 20. convegno Italian Society of Neurochemistry (SINS) tenutosi a Torino : 14-17 September nel 2023.

STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP) mutants as a key factor on TATA-box binding protein (TBP) behaviour in digenic spinocerebellar ataxia type 17 (SCA17-DI)

P. Pramaggiore
Co-primo
;
S. Magri
Co-primo
;
M. Chierichetti;P. Rusmini;V. Ferrari;B. Tedesco;M. Cozzi;E. Casarotto;V. Crippa;M. Galbiati;L. Cornaggia;G. Patelli;A. Poletti
Co-ultimo
;
R. Cristofani
Co-ultimo
2023

Abstract

Spinocerebellar ataxias (SCAs) are hereditary, progressive and fatal, very heterogenous neurodegenerative diseases (NDs). SCA type 17 (SCA17) is characterized by the presence of expanded CAG nucleotide repeats of the TATA-box binding (TBP) gene that codes for an abnormally long polyglutamine (polyQ) tract in the N- terminal of the protein. This leads to reduced solubility and accumulation of mutated TBP in neurons. Strikingly, TBP forms containing an intermediate polyQ tract (41-47 Qs) show incomplete penetrance (SCA17- DI), which seems to be correlated to the presence of mutations in STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP). STUB1 is an E3 ubiquitin-ligase which has a key role in the protein quality control (PQC) system. Given the hypothesis that both TBP and STUB1 may be involved in SCA17-DI, we investigated their behaviour and interplay for a deeper understanding of the underlying molecular mechanisms in the disease. Our data show a punctate distribution and insoluble protein accumulation of overexpressed elongated polyQ TBP (TBP-Q54) that it is not present in the wild type (TBP-WT) or intermediate polyQ TBP (TBP-Q43) expressing neurons. Interestingly, 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. Our preliminary findings suggest that different pathways are responsible for STUB1-mediated TBP-Qs removal based on the different sizes of the polyQ tract. Moreover, other analyses show that STUB1 SCA17-DI-linked mutations are characterized by a reduced activity on TBP clearance. Collectively, our data demonstrate that STUB1 mutations affect TBP biochemical behaviour in SCA17-DI. Therefore, our goal is to further investigate TBP and STUB1 interplay in order to better understand their pathological role in this form of ataxia, leading to a deeper knowledge of the disease. GRANTS: Fondazione Cariplo (2021-1544)
16-set-2023
Spinocerebellar ataxias; SCA; SCA-17; SCA-17DI; TBP; CHIP; STUB1; TATA-box binding protein; STIP1 Homology And U-Box Containing Protein 1; PQC; protein quality control; polyQ; polyQ diseases
Settore BIO/13 - Biologia Applicata
Società Italiana di Neuroscienze
STIP1 Homology And U-Box Containing Protein 1 (STUB1/CHIP) mutants as a key factor on TATA-box binding protein (TBP) behaviour in digenic spinocerebellar ataxia type 17 (SCA17-DI) / P. Pramaggiore, S. Magri, M. Chierichetti, P. Rusmini, V. Ferrari, B. Tedesco, M. Cozzi, E. Casarotto, V. Crippa, M. Galbiati, L. Cornaggia, G. Patelli, D. Di Bella, F. Taroni, A. Poletti, R. Cristofani. ((Intervento presentato al 20. convegno Italian Society of Neurochemistry (SINS) tenutosi a Torino : 14-17 September nel 2023.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1002228
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