Dysfunction of the ubiquitin ligase Ube3a might be associated with synaptic pathophysiology in a mouse model of Huntington’s disease

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Huntington’s disease (HD) is a hereditary  neurodegenerative disorder characterized by  progressive cognitive, psychiatric and motor  symptoms. The disease is caused by  abnormal expansion of CAG repeats in the  gene encoding huntingtin. But how the  mutant huntingtin leads to early cognitive  deficits in HD is poorly understood. Here we demonstrate that the ubiquitin ligase Ube3a,  which is implicated in synaptic plasticity and involved in the clearance of misfolded  polyglutamine protein, strongly recruits to  the mutant huntingtin nuclear aggregates  resulting in significant loss of its functional  pool in different regions of HD mice brain.  Interestingly, the Arc, one of the substrates  of Ube3a linked with synaptic plasticity is  also associated with nuclear aggregates,  although its synaptic level is increased in the
hippocampus and cortex of HD mice brain.
Different regions of HD mice brain also  exhibits decreased levels of AMPA receptors  and various pre and post synaptic proteins,  which could be due to the partial loss of  function of Ube3a. Transient expression of  mutant huntingtin in mouse primary cortical  neurons further demonstrates recruitment of  Ube3a into mutant huntingtin aggregates,
increased accumulation of Arc and  decreased numbers of GluR1 puncta in the  neuronal processes. Altogether, our results  suggest that the loss of function of Ube3a  might be associated with the synaptic  abnormalities observed in HD.

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Source: The Journal of Biological Chemistry

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