# SCA7 neurodegeneration: Molecular epigenetic basis and therapy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2024 · $503,195

## Abstract

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.

## Key facts

- **NIH application ID:** 10812778
- **Project number:** 2R01EY014061-19
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** ALBERT R LA SPADA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,195
- **Award type:** 2
- **Project period:** 2002-05-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812778

## Citation

> US National Institutes of Health, RePORTER application 10812778, SCA7 neurodegeneration: Molecular epigenetic basis and therapy (2R01EY014061-19). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10812778. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*