title: Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. The multifaceted aspects of a single mutation.
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.
authors.affiliation: Laboratory of Neurogenetics, Department of Molecular Neuroscience, UCL Institute of Neurology London, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.affiliation: Laboratory of Neurogenetics, Institute of Translational Pharmacology, National Research Council of Italy Rome, Italy.
authors.forename: Elide
authors.initials: E
authors.lastname: Mantuano
authors.affiliation: Laboratory of Neurogenetics, Institute of Translational Pharmacology, National Research Council of Italy Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Frontali
authors.affiliation: Laboratory of Neurogenetics, Institute of Translational Pharmacology, National Research Council of Italy Rome, Italy.
authors.forename: Liana
authors.initials: L
authors.lastname: Veneziano
keywords: CACNA1A; CaV2.1; P/Q type calcium channel; SCA6; Spinocerebellar Ataxia type 6; channelopathy; polyglutamine disorder