Machado-Joseph Disease: A Stress Combating Deubiquitylating Enzyme Changing Sides

Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant inheritable neurodegenerative disorder. After a long pre-symptomatic period, this late-onset disease progressively disables patients and typically leads to premature death. Neuronal loss in specific regions of the cerebellum, brainstem and basal ganglia as well as the spinal cord explains the spectra of debilitating neurological symptoms, most strikingly progressive limb, and gait ataxia. The genetic cause of MJD is a polyglutamine (polyQ) repeat expansion in the gene that encodes ataxin-3. This polyQ-containing protein displays a well-defined catalytic activity as ataxin-3 is a deubiquitylating enzyme that removes and disassembles ubiquitin chains from specific substrates. While mutant ataxin-3 with an expanded polyQ repeat induces cellular stress due to its propensity to aggregate, the native functions of wild-type ataxin-3 are linked to the cellular countermeasures against the very same stress conditions inflicted by polyQ-containing and other aggregation-prone proteins. Hence, a mixture of gain-of-function and loss-of-function mechanisms are likely to contribute to the neuronal demise observed in MJD. In this review, we discuss the intimate link between ataxin-3 and cellular stress and its relevance for therapeutic intervention in MJD.