Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42

Hashiguchi, Shunta; Doi, Hiroshi; Kunii, Misako; Nakamura, Yukihiro; Shimuta, Misa; Suzuki, Etsuko; Koyano, Shigeru; Okubo, Masaki; Kishida, Hitaru; Shiina, Masaaki; Ogata, Kazuhiro; Hirashima, Fumiko; Inoue, Yoshiya; Kubota, Shohei; Hayashi, Noriko; Nakamura, Hajime; Takahashi, Keita; Katsumoto, Atsuko; Tada, Mikiko; Tanaka, Kenichi; Sasaoka, Toshikuni; Miyatake, Satoko; Miyake, Noriko; Saitsu, Hirotomo; Sato, Nozomu; Ozaki, Kokoro; Ohta, Keizo; Yokota, Takanori; Mizusawa, Hidehiro; Mitsui, Jun; Ishiura, Hiroyuki; Yoshimura, Junichi; Morishita, Shinichi; Tsuji, Shoji; Takeuchi, Hideyuki; Ishikawa, Kinya; Matsumoto, Naomichi; Ishikawa, Takeo; Tanaka, Fumiaki

doi:10.1016/j.nbd.2019.104516

Cited by 22 publications

(31 citation statements)

References 50 publications

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“…Cacna1g-Arg1723His mice showed an adult-onset ataxic phenotype concomitant with cerebellar atrophy and Purkinje loss, as reported in human SCA42. Furthermore, Cacna1g-Arg1723His Purkinje cells displayed a change in the voltage-dependence of T-type Ca 2+ channels which strongly impact on their excitability [77]. Interestingly, Hashiguchi's study also described that Arg1723His mutation altered the resonance properties of IO neurons, a result that has also been reported in Ca v 3.1 KO mice [78,79].…”

Section: Mutations In the Cacna1g Genementioning

confidence: 76%

“…Recent findings on SCA42 using whole-exosome sequencing in HEK293T cells found that arginine-to-histidine change in CACNA1G gene was able to determine a positive shift of T-type Ca 2+ channel voltage-dependence [65]. In order to elucidate whether this point mutation is implicated in the SCA42 phenotype, a new transgenic (Cacna1g-Arg1723His) mouse model, harboring the same mutation identified in the SCA42 families, has been generated [77]. Cacna1g-Arg1723His mice showed an adult-onset ataxic phenotype concomitant with cerebellar atrophy and Purkinje loss, as reported in human SCA42.…”

Section: Mutations In the Cacna1g Genementioning

confidence: 99%

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Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Prestori

Moccia

D’Angelo

2019

IJMS

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Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

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Section: Mutations In the Cacna1g Genementioning

confidence: 76%

Section: Mutations In the Cacna1g Genementioning

confidence: 99%

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Prestori

Moccia

D’Angelo

2019

IJMS

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“…We may speculate that the pathogenic effect of the V399L mutation emerges via its interaction with auxiliary subunits (see discussion of Chapter 3) or has an effect on neuronal firing as in the case of SCA42, where the R1723H mutation in Cav3.1 with mild effect on channel activity does significantly affect neuronal firing frequency (Hashiguchi et al, 2019). Our work on the V399L mutation stresses the importance to handle the information obtained from human genetic studies with care before a conclusion can be made on pathogenicity.…”

Section: 2mentioning

confidence: 99%

“…The effect of loss-of-function mutations in the Kv4.3 channel on neuronal excitability of Purkinje cells Channelopathies including SCA19/22 (e.g., episodic ataxia type 2, SCA6, SCA13, SCA15/16/29, SCA27, SCA41, and SCA42) which result in cerebellar dysfunction are caused by genetic variations in genes encoding calcium, potassium, and sodium channels . Several of these malfunctioning mutant ion channels lead to the development of ataxia as a result of improper altered firing activity of PCs, in some cases complicated by a neuronal development component (Becker et al, 2009;Hashiguchi et al, 2019;Irie, Matsuzaki, Sekino, & Hirai, 2014;Issa, Mazzochi, Mock, & Papazian, 2011). For instance, in the case of mutations in CACNA1A encoding the voltage-gated calcium channel Cav2.1, gain-and loss-of-function mutations cause cerebellar ataxia by disrupting the firing pattern of PCs (Fletcher et al, 1996;Gao et al, 2012).…”

Section: 3mentioning

confidence: 99%

“…Since both an increase and a reduction of calcium influx cause malfunctioning of PCs, another study suggested that a narrow window of Ca 2+ concentrations needs to be maintained in order to ensure the proper functioning of PCs (De Zeeuw et al, 2011). In the case of Cav3.1 channel, the R1723H mutation causes a modest shift in the voltage activation of the channel which is sufficient to alter the firing of PCs and lead to the development of SCA42 (Hashiguchi et al, 2019).…”

Section: 3mentioning

confidence: 99%

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A comprehensive study of the voltage gated potassium channel Kv4.3: from functional analysis to molecular dynamics modelling

Tiecher¹

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T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease

Matthews

Puryear

Correia

et al. 2023

Ann Clin Transl Neurol

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Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond.

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Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42

Cited by 22 publications

References 50 publications

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

A comprehensive study of the voltage gated potassium channel Kv4.3: from functional analysis to molecular dynamics modelling

T‐type calcium channels as therapeutic targets in essential tremor and Parkinson's disease

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