Cerebellar degeneration and prevention of symptom progression in a mouse model of spinocerebellar ataxia type 7
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Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by progressive cerebellar, brainstem, and retinal degeneration. SCA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. Ataxin-7 is widely expressed, but certain neural populations, including cerebellar Purkinje cells (PCs), are selectively vulnerable to the mutation. Previous SCA7 mouse models have demonstrated multiple cell types must express mutant ataxin-7 to cause ataxia and non-cell autonomous PC degeneration. To further define specific cellular roles in SCA7 pathogenesis, we generated a novel SCA7 mouse model that expresses a loxP-flanked ataxin-7-92Q cDNA under the control of the murine prion protein (PrP) promoter in a bacterial artificial chromosome (BAC). To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, we crossed PrP-floxed-SCA7-92Q BAC mice with Gfa2-Cre mice (to direct Cre to Bergmann glia (BG)) or Pcp2-Cre mice (to direct Cre to PCs and inferior olive (IO)). Excision of ataxin-7 from BG partially rescued behavioral abnormalities, but did not prevent BG process loss or molecular layer thinning. Excision of ataxin-7 from PCs and IO provided significantly greater rescue and prevented both pathological changes, revealing a non-cell autonomous basis for BG pathology. Prevention of mutant ataxin-7 expression in BG, PCs, and IO delayed symptom onset by half the lifespan (20 weeks) of PrP-floxed-SCA7-92Q BAC mice. Thus, cerebellar PCs and BG, and IO neurons in the brainstem, are the major cellular contributors to SCA7 pathogenesis. To determine whether neurological dysfunction is reversible during the progressive phase of SCA7 disease, we crossed the PrP-floxed-SCA7-92Q BAC mouse line to transgenic mice that ubiquitously express tamoxifen-inducible Cre recombinase. Administration of tamoxifen citrate four weeks after symptom onset globally inactivated mutant ataxin-7 expression, which prevented further symptom progression and restored some motor function. Tamoxifen treatment did not significantly alter molecular layer thinning and BG process loss, but it prevented the redistribution of climbing fiber terminals and reduced the number of PC nuclei containing ataxin-7 aggregates. Our results demonstrate that suppression of polyQ-ataxin-7 gene expression prevents further symptom progression, even when initiated after symptom onset and at a time when some histopathological changes cannot be reversed.
- Neuroscience