Thursday, March 13, 2025
3/13/2025
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurological disorder characterized by cerebellar and retinal degeneration. SCA7 is caused by CAG/polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. Over 20 years ago, we linked SCA7 retinal degeneration to transcription dysregulation, and then discovered that ataxin-7 is a core component of the transcription co-activator complex STAGA, which possesses intrinsic histone acetyltransferase (GCN5) and histone deubiquitinase (USP22) activity. In the last funding cycle, we set out to determine the molecular basis of SCA7 cerebellar and retinal degeneration by examining the transcriptome and epigenome, and thereby implicated DNA damage, metabolic dysregulation, mitochondrial abnormalities, and calcium dyshomeostasis in SCA7 disease pathogenesis. To obtain a more complete understanding of the SCA7 disease process in cerebellum and retina, we are now pursing single-cell transcriptome and epigenome analysis in the highly representative SCA7 266Q knock-in mouse model. Employing a novel Purkinje cell-enriched single nucleus (sn)RNA-seq method, we discovered altered synaptic organization and excitatory-inhibitory balance in presymptomatic SCA7 mice. Bioinformatics analysis revealed dramatic dysregulation of normal aldolase-C / zebrin-II expression patterning and corresponding parasagittal striping in presymptomatic SCA7 mice, and based upon analysis of related SCA polyQ disease model mice, we established that altered cerebellar neurodevelopment is a shared disease feature across various polyQ cerebellar ataxias. Here we propose to define the epigenetic basis for transcriptional alterations in SCA7 retinal degeneration and cerebellar degeneration by performing snRNA-seq and snATAC-seq on retina and cerebellum samples from SCA7 mice, and classifying DEGs and DARs from different cell types to reveal genes and regulatory elements that underlie the molecular pathology. We will pursue Transcription Factor Binding Site analysis to define transcription factors (TFs) whose dysregulation may contribute to SCA7, and we will confirm candidate TF and epigenetic pathology by directed experimentation. We will modulate the expression or function of implicated TFs in SCA7 knock-in model mice to determine if such interventions can prevent or significantly ameliorate SCA7 neurodegeneration. This validation work will employ an in vivo epigenetic rescue strategy involving use of Cre-inducible dCas9-p300 (or -KRAB) mice, and we will determine if epigenetic rescue can ameliorate SCA7 retinal and cerebellar pathology, including disrupted zebrin-II patterning. Finally, we will test if interventions found to rescue SCA7 cerebellar disease can be applied to related polyQ SCAs.
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