Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells
| العنوان: | Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells |
|---|---|
| المؤلفون: | Sara Duarte-Silva, Ana Freitas, João B. Relvas, Patrícia Maciel, Elsa Logarinho, Margarida Isabel Barros Coelho Martins, Anabela Silva-Fernandes, Maria do Carmo Costa, Peter Heutink, André T. Lopes, Andreia Neves-Carvalho, Henry L. Paulson, Sofia Cravino Serra |
| المساهمون: | Universidade do Minho |
| المصدر: | Human molecular genetics 24(1), 100-117 (2014). doi:10.1093/hmg/ddu422 Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| بيانات النشر: | Oxford Univ. Press, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cellular differentiation, metabolism [Hippocampus], Integrin alpha5, Hippocampus, PC12 Cells, Small hairpin RNA, Mice, Ganglia, Spinal, Atxn3 protein, mouse, metabolism [Peptides], metabolism [Transcription Factors], Ataxin-3, Genetics (clinical), Cells, Cultured, metabolism [Repressor Proteins], Neurons, biology, Neurodegeneration, Nuclear Proteins, Cell Differentiation, General Medicine, Articles, 3. Good health, Cell biology, metabolism [Neurons], metabolism [Integrin alpha5], Atxn3 protein, rat, metabolism [Nuclear Proteins], congenital, hereditary, and neonatal diseases and abnormalities, Proteasome Endopeptidase Complex, Integrin, Nerve Tissue Proteins, ddc:570, Genetics, medicine, Gene silencing, Animals, Humans, metabolism [Proteasome Endopeptidase Complex], Rats, Wistar, Molecular Biology, Science & Technology, metabolism [Nerve Tissue Proteins], cytology [Ganglia, Spinal], HEK 293 cells, ATXN3 protein, human, medicine.disease, Rats, Repressor Proteins, HEK293 Cells, Ataxin, cytology [Hippocampus], Immunology, Neuron differentiation, biology.protein, Peptides, polyglutamine, metabolism [Ganglia, Spinal], Transcription Factors |
| الوصف: | The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado–Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of a5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration. National Institutes of Health (NIH) ‘(R01NS038712) Fundação para a Ciência e a Tecnologia (FCT) and COMPETE through the project ‘(PTDC/SAU-GMG/ 101572/2008) Fundação para a Ciência e a Tecnologia (FCT) - fellowships SFRH/BD/51059/2010, SFRH/BD/ 78388/2011 and SFRH/BPD/91562/2012 |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b8d8786341c3956f7379a76ec5f8d33Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0b8d8786341c3956f7379a76ec5f8d33 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |