Spinocerebellar Ataxia Type 7: From Mechanistic Pathways to Therapeutic Opportunities

Spinocerebellar ataxiaSpinocerebellar ataxia (SCA) type 7 (SCA7) is a cerebellar and retinal neurodegenerative diseaseNeurodegenerative diseases caused by a CAG/polyglutamine (polyQ)Polyglutamine (polyQ) expansion mutation in the ataxin-7 (ATXN7)Ataxin-7 (ATXN7) gene. PolyQ-expanded ataxin-7Ataxin-7 (ATXN7) protein interferes with the histone modification activity of the STAGA co-activator complex and consequently alters the expression of STAGA-regulated genes. In the SCA7 pathogenic cascade, epigenetic dysregulation of the DNA repair interactome, combined with increased oxidative stress, leads to the accumulation of DNA damageDNA damage and PARP1-mediated depletion of nicotinamide adenine dinucleotide (NAD+) levels. Subsequent breakdown of the SIRT1Sirtuin 1 (SIRT1)/NAD+—PPARPPARsγ/PGC-1α transcriptional regulatory axis, arising from NAD+ depletion, results in altered expression of calciumCalcium homeostasis genes, culminating in neuronal dysfunction and death. Here, we describe the current mechanistic understanding of SCA7, highlighting recent advances in this field. Based upon our understanding of the cellular and molecular basis of SCA7 disease pathogenesisPathogeneses, we delineate both known and prospective therapeutic targets and treatmentTreatments strategies that could ameliorate polyQ-expanded ataxin-7Ataxin-7 (ATXN7) neurotoxicity, including recent progress toward an antisense oligonucleotideAntisense oligonucleotide (ASO) therapyTherapies directed against ATXN7Ataxin-7 (ATXN7) mRNA. In the near future, preclinical and clinical exploration of these therapeutic opportunities may yield a highly effective treatmentTreatments for SCA7.