Targeting the VCP-binding motif of ataxin-3 improves phenotypes in Drosophila models of Spinocerebellar Ataxia Type 3

Neurobiology of Disease

卷:160

Matthew V. Prifti¹  Sean L. Johnson²  Kozeta Libohova²  Sokol V. Todi²  Wei-Ling Tsou²  Alyson L. Sujkowski²  Jessica R. Blount² 

[1] Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA;

[2] Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA;

关键词: AAA ATPase;    Ataxia;    Ataxin-3;    Deubiquitinase;    Drosophila;    Machado-Joseph Disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

Of the family of polyglutamine (polyQ) neurodegenerative diseases, Spinocerebellar Ataxia Type 3 (SCA3) is the most common. Like other polyQ diseases, SCA3 stems from abnormal expansions in the CAG triplet repeat of its disease gene resulting in elongated polyQ repeats within its protein, ataxin-3. Various ataxin-3 protein domains contribute to its toxicity, including the valosin-containing protein (VCP)-binding motif (VBM). We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity. These findings led us to explore the impact of targeting the SCA3 protein by utilizing a decoy protein comprising the N-terminus of VCP (N-VCP) that binds ataxin-3's VBM. The notion was that N-VCP would reduce binding of ataxin-3 to VCP, decreasing its aggregation and toxicity. We found that expression of N-VCP in Drosophila melanogaster models of SCA3 ameliorated various phenotypes, coincident with reduced ataxin-3 aggregation. This protective effect was specific to pathogenic ataxin-3 and depended on its VBM. Increasing the amount of N-VCP resulted in further phenotype improvement. Our work highlights the protective potential of targeting the VCP-ataxin-3 interaction in SCA3, a key finding in the search for therapeutic opportunities for this incurable disorder.

【 授权许可】

Unknown