NEI Sayer Lecture: Clinical features and molecular basis of the cerebellar-retinal degenerative disorder SpinoCerebellar Ataxia type 7: From mechanism to therapy

NEI Sayer Lecture Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder characterized by cerebellar and retinal degeneration. SCA7 patients develop atrophy of the cerebellar cortex and the brainstem, and exhibit extensive loss of cerebellar Purkinje cells. An important feature of SCA7, that allows it to be distinguished from the 40+ other SCAs, is retinal degeneration. Full field electroretinograms of SCA7 patients reveal marked dysfunction of cone photoreceptor cells prior to rod photoreceptor abnormalities, establishing SCA7 as a cone-rod dystrophy. As retinal disease progresses, rod photoreceptors become involved, and the visual impairment proceeds to complete blindness. SCA7 is a neurodegenerative disorder with a broad phenotypic spectrum – some SCA7 patients present as children and succumb to disease in less than a decade, while other patients remain undiagnosed until middle age and display a slowly progressive course. SCA7 is caused by CAG/polyglutamine (polyQ) repeat expansions in the ataxin-7 gene, and is therefore one of nine polyQ neurodegenerative disorders. To determine the molecular and mechanistic basis of SCA7 disease pathogenesis, we developed a mouse model of SCA7 cone-rod dystrophy, and implicated transcriptional dysregulation in the retinal degeneration. This work led us to define ataxin-7 as a transcription factor, and identify ataxin-7 as a core component of the STAGA co-activator complex. As incorporation of polyQ-expanded ataxin-7...
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