Phosphorylation reduces the neurotoxic effects of a protein mutated in Machado-Joseph disease (MJD), Matos et al. reveal.
Ataxin-3 is a ubiquitously expressed deubiquitinase that is proposed to function in a variety of cellular pathways. In MJD (also known as spinocerebellar ataxia type 3), a polyglutamine tract in ataxin-3’s C-terminal tail becomes abnormally expanded, causing the protein to aggregate and induce cellular stress. Only certain populations of neurons die in MJD patients, however, suggesting that cell type–specific posttranslational modifications might affect the toxicity of expanded ataxin-3.
Matos et al. found that ataxin-3 is phosphorylated on serine 12 in cultured rat neurons, and mutating this serine to a phosphomimetic aspartate residue inhibited the enzyme’s deubiquitinase activity. Expressing an expanded version of ataxin-3 in cultured neurons induced dendritic shrinkage and a loss of both excitatory and inhibitory synapses. This effect was attenuated when serine 12 was mutated to aspartate. In contrast, mutating this serine to a nonphosphorylatable alanine residue caused normal, nonexpanded ataxin-3 to induce dendrite and synapse loss.
Despite these opposing effects on neuronal morphology, mutating serine 12 to either aspartate or alanine reduced the ability of expanded ataxin-3 to aggregate and induce neurodegeneration in rat brains. Senior author Ana Luisa Carvalho says that modulating ataxin-3 phosphorylation could be an effective way to treat MJD patients. To this end, she wants to identify the kinase that phosphorylates serine 12.