Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. The multifaceted aspects of a single mutation.

Paola Giunti,Marina Frontali,Elide Mantuano,Liana Veneziano

doi:10.3389/fncel.2015.00036

Abstract

Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, particularly in the cerebellum. The other two disorders are Episodic Ataxia type 2 (EA2), and Familial Hemiplegic Migraine type 1 (FHM1). These disorders show distinct phenotypes that often overlap but have different pathogenic mechanisms. EA2 and FHM1 are due to mutations causing, respectively, a loss and a gain of channel function. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein. This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; thus the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity. We will provide a short review for an update on the SCA6 molecular mechanism.

Highlights

It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha1 A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, in the cerebellum
Spinocerebellar Ataxia type 6 (SCA6, OMIM 183086) is a neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia sometimes preceded by an episodic phase showing dysarthria, nystagmus and vertigo (Jodice et al, 1997)
Currently, no therapy is known for SCA6, except for the use of Acetazolamide, a brain carbonic anhydrase inhibitor, that has been successfully used for Episodic Ataxia type 2 (EA2) but is possibly effective only in the episodic phase of SCA6 (Jen et al, 1998); Yabe et al (2001) suggested that this drug can temporarily reduce the severity of symptoms during the progression of the disease

Summary

CELLULAR NEUROSCIENCE

Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. Spinocerebellar Ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease characterized by late onset, slowly progressive, mostly pure cerebellar ataxia. It is one of three allelic disorders associated to CACNA1A gene, coding for the Alpha A subunit of P/Q type calcium channel Cav2.1 expressed in the brain, in the cerebellum. SCA6, instead, is associated with short expansions of a polyglutamine stretch located in the cytoplasmic C-terminal tail of the protein This domain has a relevant role in channel regulation, as well as in transcription regulation of other neuronal genes; the SCA6 CAG repeat expansion results in complex pathogenic molecular mechanisms reflecting the complex Cav2.1 C-terminus activity.

INTRODUCTION

CONCLUSIONS

Possibly responsible for the early episodic symptoms