C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity

Khare, Swati; Galeano, Kira; Zhang, Yalan; Nick, Jerelyn; Nick, Harry S.; Subramony, S. H.; Sampson, Jacinda B.; Kaczmarek, Leonard K.; Waters, Michael F.

doi:10.1007/s12311-018-0950-5

Cited by 8 publications

(4 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…The physiological function of KCNC3 in the cerebellum is well known [30]. Purkinje cells express KCNC3 in both their soma and dendrites, and KCNC3 plays a critical role in the Purkinje cell spikelet repolarization and the shaping of the complex spike [30]. Mutations in the KCNC3 gene cause cerebellar neurodegeneration and impair auditory processing, termed spinocerebellar ataxia type 13 (SCA13) [31].…”

Section: Discussionmentioning

confidence: 99%

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Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Chen

Jin

et al. 2022

Hum Genomics

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Background Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein. The pathogenic mechanism resulting in SCA1 is still unclear. Protein–protein interactions affect the function and stability of ataxin-1. Methods Wild-type and mutant ataxin-1 were expressed in HEK-293T cells. The levels of expression were assessed using real-time polymerase chain reaction (PCR) and Western blots. Co-immunoprecipitation was done in HEK-293T cells expressing exogenous wild-type and mutant ataxin-1 using anti-Flag antibody following by tandem affinity purification in order to study protein–protein interactions. The candidate interacting proteins were validated by immunoprecipitation. Chromatin immunoprecipitation and high-throughput sequencing and RNA immunoprecipitation and high-throughput sequencing were performed using HEK-293T cells expressing wild-type or mutant ataxin-1. Results In this study using HEK-293T cells, we found that wild-type ataxin-1 interacted with MCM2, GNAS, and TMEM206, while mutant ataxin-1 lost its interaction with MCM2, GNAS, and TMEM206. Two ataxin-1 binding targets containing the core GGAG or AAAT were identified in HEK-293T cells using ChIP-seq. Gene Ontology analysis of the top ataxin-1 binding genes identified SLC6A15, NTF3, KCNC3, and DNAJC6 as functional genes in neurons in vitro. Ataxin-1 also was identified as an RNA-binding protein in HEK-293T cells using RIP-seq, but the polyglutamine expansion in the ataxin-1 had no direct effects on the RNA-binding activity of ataxin-1. Conclusions An expanded polyglutamine tract in ataxin-1 might interfere with protein–protein or protein–DNA interactions but had little effect on protein–RNA interactions. This study suggested that the dysfunction of protein–protein or protein–DNA interactions is involved in the pathogenesis of SCA1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Chen

Jin

et al. 2022

Hum Genomics

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“…The physiological function of KCNC3 in the cerebellum is well known. Purkinje cells express KCNC3 in both their soma and dendrites, and KCNC3 plays a critical role in the Purkinje cell spikelet repolarization and the shaping of the complex spike [22]. Mutations in the KCNC3 gene cause cerebellar neurodegeneration and impair auditory processing, termed spinocerebellar ataxia type 13 (SCA13) [23].…”

Section: Discussionmentioning

confidence: 99%

Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Chen

Jin

et al. 2022

Preprint

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Background: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by a polyglutamine expansion in the ataxin-1 protein. The pathogenic mechanism resulting in SCA1 is still unclear. Protein-protein interactions affect the function and stability of ataxin-1.Methods: Wild type and mutant ataxin-1 were expressed in HEK-293T cells. The levels of expression were assessed using real-time polymerase chain reaction (PCR) and Western blots. Co-immunoprecipitation was done in HEK-293T cells expressing exogenous wild type and mutant ataxin-1 using anti-Flag antibody following by tandem affinity purification in order to study protein-protein interactions. The candidate interacting proteins were validated by immunoprecipitation. Chromatin immunoprecipitation and high-throughput sequencing and RNA immunoprecipitation and high-throughput sequencing were performed using HEK-293T cells expressing wild type or mutant ataxin-1.Results: In this study using HEK-293T cells, we found that wild type ataxin-1 interacted with MCM2, GNAS, and TMEM206, while mutant ataxin-1 lost its interaction with MCM2, GNAS, and TMEM206. Two ataxin-1 binding targets containing the core GGAG or AAAT were identified in HEK-293T cells using ChIP-seq. Gene Ontology analysis of the top ataxin-1 binding genes identified SLC6A15, NTF3, KCNC3, and DNAJC6 as functional genes in neurons in vitro. Ataxin-1 also was identified as an RNA binding protein in HEK-293T cells using RIP-seq, but the polyglutamine expansion in the ataxin-1 had no direct effects on the RNA binding activity of ataxin-1.Conclusions: An expanded polyglutamine tract in ataxin-1 might interfere with protein-protein or protein-DNA interactions but had little effect on protein-RNA interactions. This study suggested that the dysfunction of protein-protein or protein-DNA interactions is involved in the pathogenesis of SCA1.

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“…Mental retardation is an uncommon feature in autosomal dominant cerebellar ataxias, in contrast with the recessively-inherited forms. In addition, myoclonus and spasticity seem to be relatively prevalent findings in SCA13 [100][101][102]. The age of onset and clinical phenotype of the disease depend on the type of mutation.…”

Section: Sca13mentioning

confidence: 99%

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

Szpisjak

Zádori

Klivényi

et al. 2019

CNSNDDT

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Background & Objective: The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. Conclusion: The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year’s promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

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C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity

Cited by 8 publications

References 16 publications

Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Identification of the ataxin-1 interaction network and its impact on spinocerebellar ataxia type 1

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias

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