Hsp104 Suppresses Polyglutamine-Induced Degeneration Post Onset in a Drosophila MJD/SCA3 Model

摘要

There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. Author Summary There are no effective therapeutics for any of the neurodegenerative disorders caused by expanded polyglutamine (PolyQ) tracts including Spinocerebellar Ataxia Type-3 (SCA3). These disorders are connected with the misfolding and aggregation of proteins bearing expanded PolyQ tracts in the neurons of affected individuals. In SCA3, ataxin-3 (MJD) is the protein that bears the PolyQ expansion and forms insoluble aggregates. Here, as a therapeutic strategy we introduce Hsp104, a powerful protein disaggregase from yeast, into Drosophila models of SCA3. Hsp104 has no homologue in animals, but has an unusual ability to dissolve PolyQ aggregates in vitro , an activity that could be harnessed therapeutically. Indeed, Hsp104 suppressed degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, which accumulates in disease. However, Hsp104 enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 rescued forms of MJD unable to engage polyubiquitin or with a deletion in the deubiquitylase domain indicating that MJD-ubiquitin interactions hinder protective Hsp104 activities. Importantly, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.