Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.

Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7

“…These processes take place in mitochondria, where the role of ACCs is to transport long-chain fatty acids into mitochondria for -oxidation [52]; in fact, fatty acids have been implicated in diverse neurodegenerative diseases [50,51,53]. Furthermore, ACCs have been shown to possess diverse neuroprotective effects, including improvement of mitochondrial function, modulation of gene expression, enhancement of cholinergic neurotransmission, antioxidant activity, and membrane stabilization [18,23,45,54,55]. Thus, metabolic changes in these metabolites could be an indicator of these mechanistic alterations.…”

“…Thus, metabolic changes in these metabolites could be an indicator of these mechanistic alterations. It should be noted that the analysis of our study population is highly valuable due to the rare worldwide incidence of SCA7 (<1/100,000) [8,18]. Future longitudinal studies on larger samples of patients, as well as comparative analyses of SCA7 with other SCAs and polyQ diseases, are required to confirm the existence of disease-and even disease-stage-specific metabolites in SCA7.…”

“…EO has a rapid and aggressive course of the disease, and it is commonly associated with regression of motor milestones. At the cellular level, different processes are altered in SCA7, including transcriptional regulation, oxidative stress, mitochondrial function, protein turnover, autophagy, and cell death [9][10][11][12][13][14][15][16][17][18].…”

Dynamic modules of the coactivator SAGA in eukaryotic transcription

“…In addition to its contribution to cancer development, the DUBm subunit ATXN7 is closely related to neurodegenerative disease. An expansion of a highly conserved polyQ motif in the amino-terminal region of ATXN7 causes spinocerebellar ataxia type 7 (SCA7) 141 . Several studies have indicated that polyQ-expanded ATXN7 (polyQ-ATXN7) is incorporated into SAGA 142,143 and affects its function.…”

Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells

“…This is particularly relevant in cases where the genomic context of the mutation may have an impact on gene function and might prove useful for therapeutic development. There does, however, seem to be increasing momentum in this area with new models being proposed and refined [10][11][12].…”