title: DnaJ-1 and karyopherin α3 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 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 characterization of the first Drosophila melanogaster models of SCA6, which express the entire human α1ACT protein with a normal or expanded polyQ. The polyQ-expanded version of α1ACT 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 α1ACT-dependent degeneration and lethality, concomitant with decreased aggregation and reduced nuclear localization of the pathogenic protein. Mutating the nuclear importer karyopherin α3 also leads to reduced toxicity from pathogenic α1ACT. 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.
authors.affiliation: Department of Pharmacology.
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Hosking
authors.affiliation: Department of Pharmacology, Cancer Biology Graduate Program and.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Burr
authors.affiliation: Department of Pharmacology.
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Sutton
authors.affiliation: Department of Pharmacology.
authors.forename: Michelle
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Department of Neurology, University of Chicago School of Medicine, Chicago, IL 60637, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Neurology, University of Chicago School of Medicine, Chicago, IL 60637, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gomez
authors.affiliation: Department of Pharmacology, Cancer Biology Graduate Program and Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, USA and stodi@med.wayne.edu.
authors.forename: Sokol V
authors.initials: SV
authors.lastname: Todi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015220:Calcium Channels / Q000235:genetics*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D028901:alpha Karyopherins / Q000096:biosynthesis / Q000235:genetics*; D020864:Calcium Channels, N-Type
chemical_list: D015220:Calcium Channels; D029721:Drosophila Proteins; D050956:HSP40 Heat-Shock Proteins; D028901:alpha Karyopherins; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C494637:DnaJ-1 protein, Drosophila