Ataxic phenotype with altered Ca V 3.1 channel property in a mouse model for spinocerebellar ataxia 42
Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel Ca 3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination...
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creator | 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, Yukichi Kubota, Shun Hayashi, Noriko Nakamura, Haruko Takahashi, Keita Katsumoto, Atsuko Tada, Mikiko Tanaka, Kenichi Sasaoka, Toshikuni Miyatake, Satoko Miyake, Noriko Saitsu, Hirotomo Sato, Nozomu Ozaki, Kokoro Ohta, Kiyobumi Yokota, Takanori Mizusawa, Hidehiro Mitsui, Jun Ishiura, Hiroyuki Yoshimura, Jun Morishita, Shinichi Tsuji, Shoji Takeuchi, Hideyuki Ishikawa, Kinya Matsumoto, Naomichi Ishikawa, Taro Tanaka, Fumiaki |
description | Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel Ca
3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of Ca
3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His Ca
3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss. |
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3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of Ca
3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His Ca
3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.</description><identifier>EISSN: 1095-953X</identifier><identifier>PMID: 31229688</identifier><language>eng</language><publisher>United States</publisher><subject>Aged ; Aged, 80 and over ; Animals ; Calcium Channels, T-Type - genetics ; Calcium Channels, T-Type - metabolism ; Cerebellum - metabolism ; Cerebellum - pathology ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Phenotype ; Purkinje Cells - metabolism ; Purkinje Cells - pathology ; Spinocerebellar Ataxias - genetics ; Spinocerebellar Ataxias - metabolism ; Spinocerebellar Ataxias - pathology</subject><ispartof>Neurobiology of disease, 2019-10, Vol.130, p.104516</ispartof><rights>Copyright © 2019 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31229688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hashiguchi, Shunta</creatorcontrib><creatorcontrib>Doi, Hiroshi</creatorcontrib><creatorcontrib>Kunii, Misako</creatorcontrib><creatorcontrib>Nakamura, Yukihiro</creatorcontrib><creatorcontrib>Shimuta, Misa</creatorcontrib><creatorcontrib>Suzuki, Etsuko</creatorcontrib><creatorcontrib>Koyano, Shigeru</creatorcontrib><creatorcontrib>Okubo, Masaki</creatorcontrib><creatorcontrib>Kishida, Hitaru</creatorcontrib><creatorcontrib>Shiina, Masaaki</creatorcontrib><creatorcontrib>Ogata, Kazuhiro</creatorcontrib><creatorcontrib>Hirashima, Fumiko</creatorcontrib><creatorcontrib>Inoue, Yukichi</creatorcontrib><creatorcontrib>Kubota, Shun</creatorcontrib><creatorcontrib>Hayashi, Noriko</creatorcontrib><creatorcontrib>Nakamura, Haruko</creatorcontrib><creatorcontrib>Takahashi, Keita</creatorcontrib><creatorcontrib>Katsumoto, Atsuko</creatorcontrib><creatorcontrib>Tada, Mikiko</creatorcontrib><creatorcontrib>Tanaka, Kenichi</creatorcontrib><creatorcontrib>Sasaoka, Toshikuni</creatorcontrib><creatorcontrib>Miyatake, Satoko</creatorcontrib><creatorcontrib>Miyake, Noriko</creatorcontrib><creatorcontrib>Saitsu, Hirotomo</creatorcontrib><creatorcontrib>Sato, Nozomu</creatorcontrib><creatorcontrib>Ozaki, Kokoro</creatorcontrib><creatorcontrib>Ohta, Kiyobumi</creatorcontrib><creatorcontrib>Yokota, Takanori</creatorcontrib><creatorcontrib>Mizusawa, Hidehiro</creatorcontrib><creatorcontrib>Mitsui, Jun</creatorcontrib><creatorcontrib>Ishiura, Hiroyuki</creatorcontrib><creatorcontrib>Yoshimura, Jun</creatorcontrib><creatorcontrib>Morishita, Shinichi</creatorcontrib><creatorcontrib>Tsuji, Shoji</creatorcontrib><creatorcontrib>Takeuchi, Hideyuki</creatorcontrib><creatorcontrib>Ishikawa, Kinya</creatorcontrib><creatorcontrib>Matsumoto, Naomichi</creatorcontrib><creatorcontrib>Ishikawa, Taro</creatorcontrib><creatorcontrib>Tanaka, Fumiaki</creatorcontrib><title>Ataxic phenotype with altered Ca V 3.1 channel property in a mouse model for spinocerebellar ataxia 42</title><title>Neurobiology of disease</title><addtitle>Neurobiol Dis</addtitle><description>Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel Ca
3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of Ca
3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His Ca
3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>Calcium Channels, T-Type - genetics</subject><subject>Calcium Channels, T-Type - metabolism</subject><subject>Cerebellum - metabolism</subject><subject>Cerebellum - pathology</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Phenotype</subject><subject>Purkinje Cells - metabolism</subject><subject>Purkinje Cells - pathology</subject><subject>Spinocerebellar Ataxias - genetics</subject><subject>Spinocerebellar Ataxias - metabolism</subject><subject>Spinocerebellar Ataxias - pathology</subject><issn>1095-953X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjk0KwjAUhIMg_l9B3gUqTWPVLqUoHkDEXXm2rzSSJiGJaG9vBV27mVnMN8MM2ITHWRplqbiO2dT7exxznmbbERsLniTZZrebsHof8CVLsA1pEzpL8JShAVSBHFWQI1xArDiUDWpNCqwzllzoQGpAaM3DU69Vn9TGgbdSm7Jv3kgpdICfcYR1MmfDGpWnxddnbHk8nPNTZB-3lqrCOtmi64rfMfEXeANZbkNo</recordid><startdate>201910</startdate><enddate>201910</enddate><creator>Hashiguchi, Shunta</creator><creator>Doi, Hiroshi</creator><creator>Kunii, Misako</creator><creator>Nakamura, Yukihiro</creator><creator>Shimuta, Misa</creator><creator>Suzuki, Etsuko</creator><creator>Koyano, Shigeru</creator><creator>Okubo, Masaki</creator><creator>Kishida, Hitaru</creator><creator>Shiina, Masaaki</creator><creator>Ogata, Kazuhiro</creator><creator>Hirashima, Fumiko</creator><creator>Inoue, Yukichi</creator><creator>Kubota, Shun</creator><creator>Hayashi, Noriko</creator><creator>Nakamura, Haruko</creator><creator>Takahashi, Keita</creator><creator>Katsumoto, Atsuko</creator><creator>Tada, Mikiko</creator><creator>Tanaka, Kenichi</creator><creator>Sasaoka, Toshikuni</creator><creator>Miyatake, Satoko</creator><creator>Miyake, Noriko</creator><creator>Saitsu, Hirotomo</creator><creator>Sato, Nozomu</creator><creator>Ozaki, Kokoro</creator><creator>Ohta, Kiyobumi</creator><creator>Yokota, Takanori</creator><creator>Mizusawa, Hidehiro</creator><creator>Mitsui, Jun</creator><creator>Ishiura, Hiroyuki</creator><creator>Yoshimura, Jun</creator><creator>Morishita, Shinichi</creator><creator>Tsuji, Shoji</creator><creator>Takeuchi, Hideyuki</creator><creator>Ishikawa, Kinya</creator><creator>Matsumoto, Naomichi</creator><creator>Ishikawa, Taro</creator><creator>Tanaka, Fumiaki</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>201910</creationdate><title>Ataxic phenotype with altered Ca V 3.1 channel property in a mouse model for spinocerebellar ataxia 42</title><author>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, Yukichi ; Kubota, Shun ; Hayashi, Noriko ; Nakamura, Haruko ; Takahashi, Keita ; Katsumoto, Atsuko ; Tada, Mikiko ; Tanaka, Kenichi ; Sasaoka, Toshikuni ; Miyatake, Satoko ; Miyake, Noriko ; Saitsu, Hirotomo ; Sato, Nozomu ; Ozaki, Kokoro ; Ohta, Kiyobumi ; Yokota, Takanori ; Mizusawa, Hidehiro ; Mitsui, Jun ; Ishiura, Hiroyuki ; Yoshimura, Jun ; Morishita, Shinichi ; Tsuji, Shoji ; Takeuchi, Hideyuki ; Ishikawa, Kinya ; Matsumoto, Naomichi ; Ishikawa, Taro ; Tanaka, Fumiaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_312296883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Animals</topic><topic>Calcium Channels, T-Type - genetics</topic><topic>Calcium Channels, T-Type - metabolism</topic><topic>Cerebellum - metabolism</topic><topic>Cerebellum - pathology</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Phenotype</topic><topic>Purkinje Cells - metabolism</topic><topic>Purkinje Cells - pathology</topic><topic>Spinocerebellar Ataxias - genetics</topic><topic>Spinocerebellar Ataxias - metabolism</topic><topic>Spinocerebellar Ataxias - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hashiguchi, Shunta</creatorcontrib><creatorcontrib>Doi, Hiroshi</creatorcontrib><creatorcontrib>Kunii, Misako</creatorcontrib><creatorcontrib>Nakamura, Yukihiro</creatorcontrib><creatorcontrib>Shimuta, Misa</creatorcontrib><creatorcontrib>Suzuki, Etsuko</creatorcontrib><creatorcontrib>Koyano, Shigeru</creatorcontrib><creatorcontrib>Okubo, Masaki</creatorcontrib><creatorcontrib>Kishida, Hitaru</creatorcontrib><creatorcontrib>Shiina, Masaaki</creatorcontrib><creatorcontrib>Ogata, Kazuhiro</creatorcontrib><creatorcontrib>Hirashima, Fumiko</creatorcontrib><creatorcontrib>Inoue, Yukichi</creatorcontrib><creatorcontrib>Kubota, Shun</creatorcontrib><creatorcontrib>Hayashi, Noriko</creatorcontrib><creatorcontrib>Nakamura, Haruko</creatorcontrib><creatorcontrib>Takahashi, Keita</creatorcontrib><creatorcontrib>Katsumoto, Atsuko</creatorcontrib><creatorcontrib>Tada, Mikiko</creatorcontrib><creatorcontrib>Tanaka, Kenichi</creatorcontrib><creatorcontrib>Sasaoka, Toshikuni</creatorcontrib><creatorcontrib>Miyatake, Satoko</creatorcontrib><creatorcontrib>Miyake, Noriko</creatorcontrib><creatorcontrib>Saitsu, Hirotomo</creatorcontrib><creatorcontrib>Sato, Nozomu</creatorcontrib><creatorcontrib>Ozaki, Kokoro</creatorcontrib><creatorcontrib>Ohta, Kiyobumi</creatorcontrib><creatorcontrib>Yokota, Takanori</creatorcontrib><creatorcontrib>Mizusawa, Hidehiro</creatorcontrib><creatorcontrib>Mitsui, Jun</creatorcontrib><creatorcontrib>Ishiura, Hiroyuki</creatorcontrib><creatorcontrib>Yoshimura, Jun</creatorcontrib><creatorcontrib>Morishita, Shinichi</creatorcontrib><creatorcontrib>Tsuji, Shoji</creatorcontrib><creatorcontrib>Takeuchi, Hideyuki</creatorcontrib><creatorcontrib>Ishikawa, Kinya</creatorcontrib><creatorcontrib>Matsumoto, Naomichi</creatorcontrib><creatorcontrib>Ishikawa, Taro</creatorcontrib><creatorcontrib>Tanaka, Fumiaki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Neurobiology of disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hashiguchi, Shunta</au><au>Doi, Hiroshi</au><au>Kunii, Misako</au><au>Nakamura, Yukihiro</au><au>Shimuta, Misa</au><au>Suzuki, Etsuko</au><au>Koyano, Shigeru</au><au>Okubo, Masaki</au><au>Kishida, Hitaru</au><au>Shiina, Masaaki</au><au>Ogata, Kazuhiro</au><au>Hirashima, Fumiko</au><au>Inoue, Yukichi</au><au>Kubota, Shun</au><au>Hayashi, Noriko</au><au>Nakamura, Haruko</au><au>Takahashi, Keita</au><au>Katsumoto, Atsuko</au><au>Tada, Mikiko</au><au>Tanaka, Kenichi</au><au>Sasaoka, Toshikuni</au><au>Miyatake, Satoko</au><au>Miyake, Noriko</au><au>Saitsu, Hirotomo</au><au>Sato, Nozomu</au><au>Ozaki, Kokoro</au><au>Ohta, Kiyobumi</au><au>Yokota, Takanori</au><au>Mizusawa, Hidehiro</au><au>Mitsui, Jun</au><au>Ishiura, Hiroyuki</au><au>Yoshimura, Jun</au><au>Morishita, Shinichi</au><au>Tsuji, Shoji</au><au>Takeuchi, Hideyuki</au><au>Ishikawa, Kinya</au><au>Matsumoto, Naomichi</au><au>Ishikawa, Taro</au><au>Tanaka, Fumiaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ataxic phenotype with altered Ca V 3.1 channel property in a mouse model for spinocerebellar ataxia 42</atitle><jtitle>Neurobiology of disease</jtitle><addtitle>Neurobiol Dis</addtitle><date>2019-10</date><risdate>2019</risdate><volume>130</volume><spage>104516</spage><pages>104516-</pages><eissn>1095-953X</eissn><abstract>Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel Ca
3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of Ca
3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His Ca
3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.</abstract><cop>United States</cop><pmid>31229688</pmid></addata></record> |
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subjects | Aged Aged, 80 and over Animals Calcium Channels, T-Type - genetics Calcium Channels, T-Type - metabolism Cerebellum - metabolism Cerebellum - pathology Disease Models, Animal Female Humans Male Mice Phenotype Purkinje Cells - metabolism Purkinje Cells - pathology Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - metabolism Spinocerebellar Ataxias - pathology |
title | Ataxic phenotype with altered Ca V 3.1 channel property in a mouse model for spinocerebellar ataxia 42 |
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