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Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2017 Oct; Vol. 106, pp. 110-123. Date of Electronic Publication: 2017 Jul 05. - Publication Year :
- 2017
-
Abstract
- Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Ca <subscript>v</subscript> 2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Ca <subscript>v</subscript> 2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Ca <subscript>v</subscript> 2.1 (Ca <subscript>v</subscript> 2.1 <superscript>R1497X</superscript> ). Phenotypic analysis of heterozygous Ca <subscript>v</subscript> 2.1 <superscript>R1497X</superscript> mice revealed ataxia associated with muscle weakness and generalized absence epilepsy. Electrophysiological studies of the cerebellar circuits in heterozygous Ca <subscript>v</subscript> 2.1 <superscript>R1497X</superscript> mice highlighted severe dysregulations in synaptic transmission of the two major excitatory inputs as well as alteration of the spontaneous activity of Purkinje cells. Moreover, these neuronal dysfunctions were associated with a strong suppression of Ca <subscript>v</subscript> 2.1 channel expression in the cerebellum of heterozygous Ca <subscript>v</subscript> 2.1 <superscript>R1497X</superscript> mice. Finally, the presence of Ca <subscript>v</subscript> 2.1 in cerebellar lipid raft microdomains was strongly impaired in heterozygous Ca <subscript>v</subscript> 2.1 <superscript>R1497X</superscript> mice. Altogether, these results reveal a pathogenic mechanism for EA2 based on a dominant negative activity of mutant channels.<br /> (Copyright © 2017. Published by Elsevier Inc.)
- Subjects :
- Animals
Ataxia pathology
Cerebellum pathology
Disease Models, Animal
Gene Knock-In Techniques
Genes, Dominant
Mice, Inbred C57BL
Mice, Transgenic
Motor Activity physiology
Muscle Weakness genetics
Muscle Weakness metabolism
Muscle Weakness pathology
Neurons pathology
Nystagmus, Pathologic pathology
Phenotype
Seizures genetics
Seizures metabolism
Seizures pathology
Synapses metabolism
Tissue Culture Techniques
Ataxia genetics
Ataxia metabolism
Calcium Channels, N-Type genetics
Calcium Channels, N-Type metabolism
Cerebellum metabolism
Neurons metabolism
Nystagmus, Pathologic genetics
Nystagmus, Pathologic metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 106
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 28688851
- Full Text :
- https://doi.org/10.1016/j.nbd.2017.07.004