The ubiquitin-proteasomesystem(UPS)controls proteinabundanceandis essential formanyaspects ofneuronal function. In ataxia (ax J) mice, profound neurological and synaptic defects result from a loss-of-function mutation in the proteasome-associated deubiquitinating enzyme Usp14, which is required for recycling ubiquitin from proteasomal substrates. Here, we show that transgenic complementation of ax J mice with neuronally expressed ubiquitin prevents early postnatal lethality, restores muscle mass, and corrects developmental and functional deficits resultingfromthe loss of Usp14,demonstratingthat ubiquitin deficiency isamajorcauseof the neurological defects observedin the ax J mice.We also show that proteasome components are normally induced during the first 2 weeks of postnatal development, which coincides with dramatic alterations in polyubiquitin chain formation. These data demonstrate a critical role for ubiquitin homeostasis in synaptic development and function, and show that ubiquitin deficiency may contribute to diseases characterized by synaptic dysfunction.
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