Gene Deregulation and Underlying Mechanisms in Spinocerebellar Ataxias With Polyglutamine Expansion

Abstract

Polyglutamine spinocerebellar ataxias (polyQ SCAs) include SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 and constitute a group of adult onset neurodegenerative disorders caused by the expansion of a CAG repeat sequence located within the coding region of specific genes, which translates into polyglutamine tract in the corresponding proteins. PolyQ SCAs are characterized by degeneration of the cerebellum and its associated structures and lead to progressive ataxia and other diverse symptoms. In recent years, gene and epigenetic deregulations have been shown to play a critical role in the pathogenesis of polyQ SCAs. Here, we provide an overview of the functions of wild type and pathogenic polyQ SCA proteins in gene regulation, describe the extent and nature of gene expression changes and their pathological consequences in diseases, and discuss potential avenues to further investigate converging and distinct disease pathways and to develop therapeutic strategies.

SCA7 mouse cerebellar pathology reveals preferential downregulation of key Purkinje cell-identity genes and shared disease signature with SCA1 and SCA2.

“…PolyQ SCAs cause damage to the cerebellum, often with high vulnerability of PCs [41]. Despite shared genetic, clinical, and neuropathological features, more is needed to identify points of intersection and divergence of the pathophysiology of polyQ SCAs [42]. While SCA proteins do not share any domain and have different cellular functions, changes in gene expression are central features in most polyQ SCAs.…”

SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

“…Finally, we show that unlike previous SCA7 mouse models, SCA7 140Q/5Q mice exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and vision functions. Therefore, SCA7 140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.Page 5/52 [42]. While SCA proteins do not share any domain and have different cellular functions, changes in gene expression are central features in most polyQ SCAs.…”

“…Page 5/52 [42]. While SCA proteins do not share any domain and have different cellular functions, changes in gene expression are central features in most polyQ SCAs.…”

New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors

“…A growing body of evidence that emerged in recent years suggests that misfolding of polyQ-containing proteins is a unifying molecular mechanism for all polyQ SCAs, which results in the formation of intracellular aggregates/inclusions in specific brain regions and, ultimately, in cell death and disease development [11,[23][24][25] (Figure 1A). It is thought that polyQ SCA pathogenesis is primarily mediated by a deleterious gain of function of the polyQ-containing mutant proteins [26].…”

“…Interestingly, all these SCAs are caused by an abnormal expansion of CAG triplet repeats located in their respective loci [4,10]. In each SCA, the expanded CAG repeats give rise to a mutant protein bearing an expanded polyglutamine (polyQ) tract [10], whose expression ultimately causes neuronal damage and extensive neurodegeneration [11]. The polyglutamine SCA diseases (polyQ SCAs) include SCA 1, 2, 3, 6, 7 and 17 and dentatorubral-pallidoluysian atrophy (DRPLA).…”