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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 into the STAGA complex interferes with the chromatin remodeling activities of this co-activator complex, we hypothesized that targeting the mutant ataxin-7 protein for destruction or preventing its production would interrupt the pathogenic cascade at its very first step, and thus chose to pursue gene silencing with an antisense oligonucleotide (ASO) as a therapeutic strategy. We recently demonstrated that ASO delivery by intravitreal injection is an effective treatment for SCA7 retinal degeneration. To determine the molecular basis for SCA7 cerebellar degeneration, we performed unbiased transcriptome profiling in SCA7 transgenic mice and have delineated a role for altered Ca++ regulation downstream of impaired sirtuin-1 function. This work has led us to uncover decreased nicotinamide adenine dinucleotide (NAD+) as the basis for sirtuin-1 dysfunction in SCA7 cerebellar degeneration, and is yielding additional therapeutic approaches for remedying SCA7 disease phenotypes in model mice and in neurons derived from SCA7 patient stem cells.
The Sayer Vision Research Lecture Series features prominent scientists conducting vision-related research. It is cohosted by NEI and the Foundation for the National Institutes of Health. The series is supported by the Sayer Vision Research Fund, which was established by NIDDK scientist Dr. Jane M. Sayer to honor her parents, Winthrop and Laura Sayer. The fund incorporates Sayer’s desire to contribute to groundbreaking medical research at NIH while raising the profile of vision research.
Albert La Spada, M.D., Ph.D., Professor of Neurology, Neurobiology and Cell Biology, Duke University School of Medicine; Director, Duke Center for Neurodegeneration & Neurotherapeutics