Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster

NEUROBIOLOGY OF DISEASE

卷:116

Article

Ristic, Gorica^1,3  Sutton, Joanna R.¹  Libohova, Kozeta¹  Todi, Sokol V.^1,2 

[1] Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA

[2] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA

[3] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA

关键词: AAA ATPase;    Ataxia;    Ataxin-3;    Deubiquitinase;    Machado-Joseph Disease;    Neurodegeneration;    Polyglutamine;    Spinocerebellar Ataxia Type 3;    VCP/p97;   

DOI  :  10.1016/j.nbd.2018.04.013

来源: Elsevier

【 摘 要 】

Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat. We examined the importance of this interaction in ataxin-3dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP-binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA -interference has a similar, protective effect to mutating the VCP-binding site of pathogenic ataxin-3. Based on in vivo pulse-chases, aggregated species of ataxin-3 are highly stable, in a manner independent of VCP-binding. Collectively, our results highlight an important role for the ataxin-3-VCP interaction in SCA3, based on a model that posits a seeding effect from VCP on pathogenic ataxin-3 aggregation and subsequent toxicity.

【 授权许可】

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