title: Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models.
abstract: 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.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Matos
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal.
authors.forename: Susana R
authors.initials: SR
authors.lastname: Louros
authors.affiliation: Instituto de Biologia Molecular e Celular and Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Almeida
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal.
authors.forename: Elisabete
authors.initials: E
authors.lastname: Ferreiro
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Ikerbasque Basque Foundation for Science and Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, E-48170 Zamudio, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Valero
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
authors.affiliation: Instituto de Biologia Molecular e Celular and Instituto de Investigação e Inovação em Saúde, University of Porto, 4200-135 Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, 3004-517 Coimbra, Portugal alc@cnc.uc.pt.
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Carvalho
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000196:embryology / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005865:Gestational Age; D057809:HEK293 Cells; D006801:Humans; D017827:Machado-Joseph Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511593:Atxn3 protein, rat