Moving Towards Therapy in SCA1: Insights from Molecular Mechanisms, Identification of Novel Targets, and Planning for Human Trials

Abstract

The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders inherited in an autosomal dominant fashion. The SCAs result in progressive gait imbalance, incoordination of the limbs, speech changes, and oculomotor dysfunction, among other symptoms. Over the past few decades, significant strides have been made in understanding the pathogenic mechanisms underlying these diseases. Although multiple efforts using a combination of genetics and pharmacology with small molecules have been made towards developing new therapeutics, no FDA approved treatment currently exists. In this review, we focus on SCA1, a common SCA subtype, in which some of the greatest advances have been made in understanding disease biology, and consequently potential therapeutic targets. Understanding of the underlying basic biology and targets of therapy in SCA1 is likely to give insight into treatment strategies in other SCAs. The diversity of the biology in the SCAs, and insight from SCA1 suggests, however, that both shared treatment strategies and specific approaches tailored to treat distinct genetic causes of SCA are likely needed for this group of devastating neurological disorders.

Functionally Relevant Maculopathy and Optic Atrophy in Spinocerebellar Ataxia Type 1

“…If confirmed in a longitudinal study, neurodegeneration of the afferent visual system measured by OCT may be used as a sensitive and easily accessible marker of global neurodegeneration in SCA-ATXN1 and-in the light of approaching therapeutic candidates-even serve as outcome candidate for clinical trials. 4,36…”

“…protein seems to be not only neurotoxic itself, but several conserved sequence motifs in the ATXN1 protein indicate a role of ATXN1 as a regulator of transcription and RNA processing, suggesting widespread pathological consequences in SCA-ATXN1. 4 Clinically, SCA-ATXN1 is typically characterized by an adult-onset cerebellar syndrome, which is typically combined with nonataxia signs. 5,6 These include most prominently pyramidal signs, but also comprise brainstem oculomotor signs, autonomic dysfunction, late cognitive impairment, and a variety of movement disorders, such as chorea, dystonia, myoclonus, and tremor.…”

Repeat Expansion Disorders: Mechanisms and Therapeutics

“…SCA1 is an autosomaldominant disorder characterized by neurodegeneration of the cerebellum, spinal cord, and brainstem and has a polyQ expansion in the ataxin-1 protein. Srinivasan and Shakkottai review the advances in understanding SCA1 disease biology and the challenges in the field to developing tailored therapeutics for the distinct SCAs [17].…”

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

“…Overall, abnormal interaction of ataxins with native partners and their assembly with new partners impair multiple cellular functions, including autophagy, ubiquitin-proteasome degradation, calcium homeostasis, mitochondrial energy production, activation of pro-apoptotic routes and synaptic neurotransmission (Figure 1C) [19,[40][41][42][43]. Overall, abnormal interaction of ataxins with native partners and their assembly with new partners impair multiple cellular functions, including autophagy, ubiquitinproteasome degradation, calcium homeostasis, mitochondrial energy production, activation of pro-apoptotic routes and synaptic neurotransmission (Figure 1C) [19,[40][41][42][43].…”

“…Overall, abnormal interaction of ataxins with native partners and their assembly with new partners impair multiple cellular functions, including autophagy, ubiquitin–proteasome degradation, calcium homeostasis, mitochondrial energy production, activation of pro-apoptotic routes and synaptic neurotransmission ( Figure 1 C) [ 19 , 40 , 41 , 42 , 43 ].…”