Publicação
Functional characterization of a new TTBK2 variant in spinocerebellar ataxia type 11
| Resumo: | Spinocerebellar ataxia type 11 (SCA11) is an autosomal dominant cerebellar ataxia caused by heterozygous frameshift variants in the tau-tubulin kinase (TTBK2) gene. However, TTBK2 missense variants are still not clearly associated with the disease. TTBK2 have been reported to regulate pro-teins related to neurodegeneration (e.g., TDP-43), microtubules (e.g., KIF2A), ciliogenesis (e.g., CEP164), transporters and receptors (e.g., BGT1 and GluK2). Currently, the pathological mechanisms behind SCA11 are not fully understood. In this study, the creation and validation of a CRISPR/Cas9 cellular model allowed to associate for the first time a TTBK2 (c.625C>T; p.L209F) missense variant with a decrease in TTBK2 protein expression and a loss-of-function effect, affecting TDP-43 phosphorylation. Moreover, alterations in autophagy markers and microtubule associated proteins were observed. The phosphoproteome data suggests a dysregulation of gene expression, translation and cytoskeleton related pathways, as well as an indication of a possible involvement of SMAD2 and SMAD4 in SCA11 pathogenesis. Overall, the TTBK2 missense variant seems to dysregulate microtubule, transcription and auto-phagy, which may affect neuronal morphogenesis and axonal transport. Further experiments must be done to find the degradation pathway responsible for TTBK2 decreased levels, understand the variant influence on autophagy, and search for other interactors in pathways linked to neurodegeneration. |
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| Autores principais: | Felício, Daniela Silva |
| Assunto: | Spinocerebellar ataxia type 11 (SCA11) Tau-tubulin kinase 2 (TTBK2) CRISPR/Cas9 Mi-crotubule dynamics Autophagy Phosphoproteomics |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Spinocerebellar ataxia type 11 (SCA11) is an autosomal dominant cerebellar ataxia caused by heterozygous frameshift variants in the tau-tubulin kinase (TTBK2) gene. However, TTBK2 missense variants are still not clearly associated with the disease. TTBK2 have been reported to regulate pro-teins related to neurodegeneration (e.g., TDP-43), microtubules (e.g., KIF2A), ciliogenesis (e.g., CEP164), transporters and receptors (e.g., BGT1 and GluK2). Currently, the pathological mechanisms behind SCA11 are not fully understood. In this study, the creation and validation of a CRISPR/Cas9 cellular model allowed to associate for the first time a TTBK2 (c.625C>T; p.L209F) missense variant with a decrease in TTBK2 protein expression and a loss-of-function effect, affecting TDP-43 phosphorylation. Moreover, alterations in autophagy markers and microtubule associated proteins were observed. The phosphoproteome data suggests a dysregulation of gene expression, translation and cytoskeleton related pathways, as well as an indication of a possible involvement of SMAD2 and SMAD4 in SCA11 pathogenesis. Overall, the TTBK2 missense variant seems to dysregulate microtubule, transcription and auto-phagy, which may affect neuronal morphogenesis and axonal transport. Further experiments must be done to find the degradation pathway responsible for TTBK2 decreased levels, understand the variant influence on autophagy, and search for other interactors in pathways linked to neurodegeneration. |
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