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DnaJ-1 and karyopherin ?3 suppress degeneration in a new Drosophila model of Spinocerebellar Ataxia Type 6.


ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) belongs to the family of CAG/polyglutamine (polyQ)-dependent neurodegenerative disorders. SCA6 is caused by abnormal expansion in a CAG trinucleotide repeat within exon 47 of CACNA1A, a bicistronic gene that encodes ?1A, a P/Q-type calcium channel subunit and a C-terminal protein, termed ?1ACT. Expansion of the CAG/polyQ region of CACNA1A occurs within ?1ACT and leads to ataxia. There are few animal models of SCA6. Here, we describe the generation and characterization of the first Drosophila melanogaster models of SCA6, which express the entire human ?1ACT protein with a normal or expanded polyQ. The polyQ-expanded version of ?1ACT recapitulates the progressively degenerative nature of SCA6 when expressed in various fly tissues and the presence of densely staining aggregates. Additional studies identify the co-chaperone DnaJ-1 as a potential therapeutic target for SCA6. Expression of DnaJ-1 potently suppresses ?1ACT-dependent degeneration and lethality, concomitant with decreased aggregation and reduced nuclear localization of the pathogenic protein. Mutating the nuclear importer karyopherin ?3 also leads to reduced toxicity from pathogenic ?1ACT. Little is known about the steps leading to degeneration in SCA6 and the means to protect neurons in this disease are lacking. Invertebrate animal models of SCA6 can expand our understanding of molecular sequelae related to degeneration in this disorder and lead to the rapid identification of cellular components that can be targeted to treat it.

SUBMITTER: Tsou WL 

PROVIDER: S-EPMC4492400 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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DnaJ-1 and karyopherin α3 suppress degeneration in a new Drosophila model of Spinocerebellar Ataxia Type 6.

Tsou Wei-Ling WL   Hosking Ryan R RR   Burr Aaron A AA   Sutton Joanna R JR   Ouyang Michelle M   Du Xiaofei X   Gomez Christopher M CM   Todi Sokol V SV  

Human molecular genetics 20150507 15


Spinocerebellar ataxia type 6 (SCA6) belongs to the family of CAG/polyglutamine (polyQ)-dependent neurodegenerative disorders. SCA6 is caused by abnormal expansion in a CAG trinucleotide repeat within exon 47 of CACNA1A, a bicistronic gene that encodes α1A, a P/Q-type calcium channel subunit and a C-terminal protein, termed α1ACT. Expansion of the CAG/polyQ region of CACNA1A occurs within α1ACT and leads to ataxia. There are few animal models of SCA6. Here, we describe the generation and charact  ...[more]

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