Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models
| العنوان: | Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models |
|---|---|
| المؤلفون: | Sandra Macedo-Ribeiro, Luís Pereira de Almeida, Bruno Almeida, Clévio Nóbrega, Susana R. Louros, Ana Luísa Carvalho, Elisabete Ferreiro, Jorge Valero, Carlos A. Matos |
| المساهمون: | Instituto de Investigação e Inovação em Saúde |
| المصدر: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP The Journal of Cell Biology Europe PubMed Central |
| بيانات النشر: | Rockefeller University Press, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Time Factors, medicine.disease_cause, Synapse, Serine, 0302 clinical medicine, Transgenic mice, Phosphorylation, Ataxin-3, Mutant ataxin-3, Research Articles, Cerebral Cortex, Neurons, Mutation, Machado-Joseph Disease, Cell biology, Expanded ataxin-3, Biochemistry, Spinocerebellar ataxia, Rat model, RNA Interference, Protein ataxin-3, Machado–Joseph disease, Signal Transduction, congenital, hereditary, and neonatal diseases and abnormalities, Molecular Sequence Data, Gestational Age, Biology, Transfection, Neuroprotection, Article, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Rats, Wistar, Cell Biology, Repeat expansion, Fibroblasts, medicine.disease, Clinical-features, Repressor Proteins, Disease Models, Animal, Polyglutamine disease, HEK293 Cells, 030104 developmental biology, nervous system, Ataxin, Machado-joseph-disease, Nerve Degeneration, Synapses, Huntingtin phosphorylation, Peptides, 030217 neurology & neurosurgery |
| الوصف: | Ataxin-3, the protein involved in spinocerebellar ataxia type 3 or Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded, and mutation of phosphorylation site S12 reduces aggregation, neuronal loss, and synapse loss. Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed to produce neuroprotection. Here, we show that ataxin-3, the protein involved in spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3–encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal loss, and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity. |
| وصف الملف: | application/pdf; text/plain |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::caa8599ef81658f39793e775da0d11fcTest https://hdl.handle.net/10216/108249Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....caa8599ef81658f39793e775da0d11fc |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |