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Published on: May 21, 2010
Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models
Carlos A Matos1, Clévio Nóbrega2, Susana R Louros2
1CNC - 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.
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.
Insights
Phosphorylation of ataxin-3 serine 12 (S12) in neurons protects against toxicity from expanded polyglutamine proteins. This finding offers a potential therapeutic strategy for spinocerebellar ataxia type 3.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Neurodegenerative diseases, such as spinocerebellar ataxia type 3 (Machado-Joseph disease), result from expanded polyglutamine sequences in proteins.
- While involved proteins are widespread, toxicity selectively affects neuronal populations.
- Endogenous cellular mechanisms may offer neuroprotection against polyglutamine expansion toxicity.
Purpose of the Study:
- To investigate the role of ataxin-3 phosphorylation at serine 12 (S12) in polyglutamine-mediated neurotoxicity.
- To determine if mimicking constitutive phosphorylation at S12 can prevent neurodegeneration.
Main Methods:
- Utilized cultured neurons to assess ataxin-3 effects on dendritic and synapse integrity.
- Investigated S12 phosphorylation in neurons and engineered a non-phosphorylatable S12 mutant.
- Administered lentiviral vectors encoding expanded ataxin-3 with or without the S12 mutation to rats.
Main Results:
- Expanded ataxin-3 caused dendritic and synapse loss in cultured neurons.
- Phosphorylation mimicry at S12 countered these neuromorphologic defects.
- In rats, the S12 mutation reduced ataxin-3 aggregation, neuronal loss, and synapse loss.
Conclusions:
- Serine 12 of ataxin-3 is crucial in the pathogenic pathways of polyglutamine expansion.
- Phosphorylation at S12 confers neuroprotection against expanded ataxin-3 toxicity.
- Targeting S12 phosphorylation presents a potential therapeutic avenue for spinocerebellar ataxia type 3.
