Ataxic phenotype with altered Ca
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 CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Hashiguchi, Shunta [verfasserIn] Doi, Hiroshi [verfasserIn] Kunii, Misako [verfasserIn] Nakamura, Yukihiro [verfasserIn] Shimuta, Misa [verfasserIn] Suzuki, Etsuko [verfasserIn] Koyano, Shigeru [verfasserIn] Okubo, Masaki [verfasserIn] Kishida, Hitaru [verfasserIn] Shiina, Masaaki [verfasserIn] Ogata, Kazuhiro [verfasserIn] Hirashima, Fumiko [verfasserIn] Inoue, Yukichi [verfasserIn] Kubota, Shun [verfasserIn] Hayashi, Noriko [verfasserIn] Nakamura, Haruko [verfasserIn] Takahashi, Keita [verfasserIn] Katsumoto, Atsuko [verfasserIn] Tada, Mikiko [verfasserIn] Tanaka, Kenichi [verfasserIn] Sasaoka, Toshikuni [verfasserIn] Miyatake, Satoko [verfasserIn] Miyake, Noriko [verfasserIn] Saitsu, Hirotomo [verfasserIn] Sato, Nozomu [verfasserIn] Ozaki, Kokoro [verfasserIn] Ohta, Kiyobumi [verfasserIn] Yokota, Takanori [verfasserIn] Mizusawa, Hidehiro [verfasserIn] Mitsui, Jun [verfasserIn] Ishiura, Hiroyuki [verfasserIn] Yoshimura, Jun [verfasserIn] Morishita, Shinichi [verfasserIn] Tsuji, Shoji [verfasserIn] Takeuchi, Hideyuki [verfasserIn] Ishikawa, Kinya [verfasserIn] Matsumoto, Naomichi [verfasserIn] Ishikawa, Taro [verfasserIn] Tanaka, Fumiaki [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2019 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Neurobiology of disease - [Amsterdam] : Elsevier, 1994, 130 |
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| Übergeordnetes Werk: |
volume:130 |
| DOI / URN: |
10.1016/j.nbd.2019.104516 |
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| Katalog-ID: |
ELV002679760 |
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| 245 | 1 | 0 | |a Ataxic phenotype with altered Ca |
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| 520 | |a 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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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| 650 | 4 | |a Spinocerebellar ataxia 42 | |
| 650 | 4 | |a CACNA1G | |
| 650 | 4 | |a Knock-in mouse | |
| 650 | 4 | |a Purkinje cell | |
| 650 | 4 | |a Inferior olivary nucleus | |
| 650 | 4 | |a Neurodegeneration | |
| 650 | 4 | |a Electrophysiology | |
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| 700 | 1 | |a Kunii, Misako |e verfasserin |4 aut | |
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| 700 | 1 | |a Morishita, Shinichi |e verfasserin |4 aut | |
| 700 | 1 | |a Tsuji, Shoji |e verfasserin |4 aut | |
| 700 | 1 | |a Takeuchi, Hideyuki |e verfasserin |0 (orcid)0000-0001-5912-7581 |4 aut | |
| 700 | 1 | |a Ishikawa, Kinya |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumoto, Naomichi |e verfasserin |4 aut | |
| 700 | 1 | |a Ishikawa, Taro |e verfasserin |4 aut | |
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10.1016/j.nbd.2019.104516 doi (DE-627)ELV002679760 (ELSEVIER)S0969-9961(19)30175-5 DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Hashiguchi, Shunta verfasserin aut Ataxic phenotype with altered Ca 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology Doi, Hiroshi verfasserin aut Kunii, Misako verfasserin aut Nakamura, Yukihiro verfasserin aut Shimuta, Misa verfasserin aut Suzuki, Etsuko verfasserin aut Koyano, Shigeru verfasserin aut Okubo, Masaki verfasserin aut Kishida, Hitaru verfasserin aut Shiina, Masaaki verfasserin aut Ogata, Kazuhiro verfasserin aut Hirashima, Fumiko verfasserin aut Inoue, Yukichi verfasserin aut Kubota, Shun verfasserin aut Hayashi, Noriko verfasserin aut Nakamura, Haruko verfasserin aut Takahashi, Keita verfasserin (orcid)0000-0002-4950-1354 aut Katsumoto, Atsuko verfasserin aut Tada, Mikiko verfasserin aut Tanaka, Kenichi verfasserin aut Sasaoka, Toshikuni verfasserin aut Miyatake, Satoko verfasserin aut Miyake, Noriko verfasserin aut Saitsu, Hirotomo verfasserin (orcid)0000-0003-0723-0960 aut Sato, Nozomu verfasserin aut Ozaki, Kokoro verfasserin (orcid)0000-0001-9081-8348 aut Ohta, Kiyobumi verfasserin aut Yokota, Takanori verfasserin aut Mizusawa, Hidehiro verfasserin aut Mitsui, Jun verfasserin aut Ishiura, Hiroyuki verfasserin aut Yoshimura, Jun verfasserin aut Morishita, Shinichi verfasserin aut Tsuji, Shoji verfasserin aut Takeuchi, Hideyuki verfasserin (orcid)0000-0001-5912-7581 aut Ishikawa, Kinya verfasserin aut Matsumoto, Naomichi verfasserin aut Ishikawa, Taro verfasserin aut Tanaka, Fumiaki verfasserin (orcid)0000-0002-9961-2693 aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 130 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:130 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 44.90 Neurologie AR 130 |
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10.1016/j.nbd.2019.104516 doi (DE-627)ELV002679760 (ELSEVIER)S0969-9961(19)30175-5 DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Hashiguchi, Shunta verfasserin aut Ataxic phenotype with altered Ca 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology Doi, Hiroshi verfasserin aut Kunii, Misako verfasserin aut Nakamura, Yukihiro verfasserin aut Shimuta, Misa verfasserin aut Suzuki, Etsuko verfasserin aut Koyano, Shigeru verfasserin aut Okubo, Masaki verfasserin aut Kishida, Hitaru verfasserin aut Shiina, Masaaki verfasserin aut Ogata, Kazuhiro verfasserin aut Hirashima, Fumiko verfasserin aut Inoue, Yukichi verfasserin aut Kubota, Shun verfasserin aut Hayashi, Noriko verfasserin aut Nakamura, Haruko verfasserin aut Takahashi, Keita verfasserin (orcid)0000-0002-4950-1354 aut Katsumoto, Atsuko verfasserin aut Tada, Mikiko verfasserin aut Tanaka, Kenichi verfasserin aut Sasaoka, Toshikuni verfasserin aut Miyatake, Satoko verfasserin aut Miyake, Noriko verfasserin aut Saitsu, Hirotomo verfasserin (orcid)0000-0003-0723-0960 aut Sato, Nozomu verfasserin aut Ozaki, Kokoro verfasserin (orcid)0000-0001-9081-8348 aut Ohta, Kiyobumi verfasserin aut Yokota, Takanori verfasserin aut Mizusawa, Hidehiro verfasserin aut Mitsui, Jun verfasserin aut Ishiura, Hiroyuki verfasserin aut Yoshimura, Jun verfasserin aut Morishita, Shinichi verfasserin aut Tsuji, Shoji verfasserin aut Takeuchi, Hideyuki verfasserin (orcid)0000-0001-5912-7581 aut Ishikawa, Kinya verfasserin aut Matsumoto, Naomichi verfasserin aut Ishikawa, Taro verfasserin aut Tanaka, Fumiaki verfasserin (orcid)0000-0002-9961-2693 aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 130 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:130 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 44.90 Neurologie AR 130 |
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10.1016/j.nbd.2019.104516 doi (DE-627)ELV002679760 (ELSEVIER)S0969-9961(19)30175-5 DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Hashiguchi, Shunta verfasserin aut Ataxic phenotype with altered Ca 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology Doi, Hiroshi verfasserin aut Kunii, Misako verfasserin aut Nakamura, Yukihiro verfasserin aut Shimuta, Misa verfasserin aut Suzuki, Etsuko verfasserin aut Koyano, Shigeru verfasserin aut Okubo, Masaki verfasserin aut Kishida, Hitaru verfasserin aut Shiina, Masaaki verfasserin aut Ogata, Kazuhiro verfasserin aut Hirashima, Fumiko verfasserin aut Inoue, Yukichi verfasserin aut Kubota, Shun verfasserin aut Hayashi, Noriko verfasserin aut Nakamura, Haruko verfasserin aut Takahashi, Keita verfasserin (orcid)0000-0002-4950-1354 aut Katsumoto, Atsuko verfasserin aut Tada, Mikiko verfasserin aut Tanaka, Kenichi verfasserin aut Sasaoka, Toshikuni verfasserin aut Miyatake, Satoko verfasserin aut Miyake, Noriko verfasserin aut Saitsu, Hirotomo verfasserin (orcid)0000-0003-0723-0960 aut Sato, Nozomu verfasserin aut Ozaki, Kokoro verfasserin (orcid)0000-0001-9081-8348 aut Ohta, Kiyobumi verfasserin aut Yokota, Takanori verfasserin aut Mizusawa, Hidehiro verfasserin aut Mitsui, Jun verfasserin aut Ishiura, Hiroyuki verfasserin aut Yoshimura, Jun verfasserin aut Morishita, Shinichi verfasserin aut Tsuji, Shoji verfasserin aut Takeuchi, Hideyuki verfasserin (orcid)0000-0001-5912-7581 aut Ishikawa, Kinya verfasserin aut Matsumoto, Naomichi verfasserin aut Ishikawa, Taro verfasserin aut Tanaka, Fumiaki verfasserin (orcid)0000-0002-9961-2693 aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 130 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:130 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 44.90 Neurologie AR 130 |
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10.1016/j.nbd.2019.104516 doi (DE-627)ELV002679760 (ELSEVIER)S0969-9961(19)30175-5 DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Hashiguchi, Shunta verfasserin aut Ataxic phenotype with altered Ca 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology Doi, Hiroshi verfasserin aut Kunii, Misako verfasserin aut Nakamura, Yukihiro verfasserin aut Shimuta, Misa verfasserin aut Suzuki, Etsuko verfasserin aut Koyano, Shigeru verfasserin aut Okubo, Masaki verfasserin aut Kishida, Hitaru verfasserin aut Shiina, Masaaki verfasserin aut Ogata, Kazuhiro verfasserin aut Hirashima, Fumiko verfasserin aut Inoue, Yukichi verfasserin aut Kubota, Shun verfasserin aut Hayashi, Noriko verfasserin aut Nakamura, Haruko verfasserin aut Takahashi, Keita verfasserin (orcid)0000-0002-4950-1354 aut Katsumoto, Atsuko verfasserin aut Tada, Mikiko verfasserin aut Tanaka, Kenichi verfasserin aut Sasaoka, Toshikuni verfasserin aut Miyatake, Satoko verfasserin aut Miyake, Noriko verfasserin aut Saitsu, Hirotomo verfasserin (orcid)0000-0003-0723-0960 aut Sato, Nozomu verfasserin aut Ozaki, Kokoro verfasserin (orcid)0000-0001-9081-8348 aut Ohta, Kiyobumi verfasserin aut Yokota, Takanori verfasserin aut Mizusawa, Hidehiro verfasserin aut Mitsui, Jun verfasserin aut Ishiura, Hiroyuki verfasserin aut Yoshimura, Jun verfasserin aut Morishita, Shinichi verfasserin aut Tsuji, Shoji verfasserin aut Takeuchi, Hideyuki verfasserin (orcid)0000-0001-5912-7581 aut Ishikawa, Kinya verfasserin aut Matsumoto, Naomichi verfasserin aut Ishikawa, Taro verfasserin aut Tanaka, Fumiaki verfasserin (orcid)0000-0002-9961-2693 aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 130 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:130 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 44.90 Neurologie AR 130 |
| allfieldsSound |
10.1016/j.nbd.2019.104516 doi (DE-627)ELV002679760 (ELSEVIER)S0969-9961(19)30175-5 DE-627 ger DE-627 rda eng 610 570 DE-600 44.90 bkl Hashiguchi, Shunta verfasserin aut Ataxic phenotype with altered Ca 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology Doi, Hiroshi verfasserin aut Kunii, Misako verfasserin aut Nakamura, Yukihiro verfasserin aut Shimuta, Misa verfasserin aut Suzuki, Etsuko verfasserin aut Koyano, Shigeru verfasserin aut Okubo, Masaki verfasserin aut Kishida, Hitaru verfasserin aut Shiina, Masaaki verfasserin aut Ogata, Kazuhiro verfasserin aut Hirashima, Fumiko verfasserin aut Inoue, Yukichi verfasserin aut Kubota, Shun verfasserin aut Hayashi, Noriko verfasserin aut Nakamura, Haruko verfasserin aut Takahashi, Keita verfasserin (orcid)0000-0002-4950-1354 aut Katsumoto, Atsuko verfasserin aut Tada, Mikiko verfasserin aut Tanaka, Kenichi verfasserin aut Sasaoka, Toshikuni verfasserin aut Miyatake, Satoko verfasserin aut Miyake, Noriko verfasserin aut Saitsu, Hirotomo verfasserin (orcid)0000-0003-0723-0960 aut Sato, Nozomu verfasserin aut Ozaki, Kokoro verfasserin (orcid)0000-0001-9081-8348 aut Ohta, Kiyobumi verfasserin aut Yokota, Takanori verfasserin aut Mizusawa, Hidehiro verfasserin aut Mitsui, Jun verfasserin aut Ishiura, Hiroyuki verfasserin aut Yoshimura, Jun verfasserin aut Morishita, Shinichi verfasserin aut Tsuji, Shoji verfasserin aut Takeuchi, Hideyuki verfasserin (orcid)0000-0001-5912-7581 aut Ishikawa, Kinya verfasserin aut Matsumoto, Naomichi verfasserin aut Ishikawa, Taro verfasserin aut Tanaka, Fumiaki verfasserin (orcid)0000-0002-9961-2693 aut Enthalten in Neurobiology of disease [Amsterdam] : Elsevier, 1994 130 Online-Ressource (DE-627)268125414 (DE-600)1471408-5 (DE-576)27234947X 1095-953X nnns volume:130 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 44.90 Neurologie AR 130 |
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Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology |
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Hashiguchi, Shunta @@aut@@ Doi, Hiroshi @@aut@@ Kunii, Misako @@aut@@ Nakamura, Yukihiro @@aut@@ Shimuta, Misa @@aut@@ Suzuki, Etsuko @@aut@@ Koyano, Shigeru @@aut@@ Okubo, Masaki @@aut@@ Kishida, Hitaru @@aut@@ Shiina, Masaaki @@aut@@ Ogata, Kazuhiro @@aut@@ Hirashima, Fumiko @@aut@@ Inoue, Yukichi @@aut@@ Kubota, Shun @@aut@@ Hayashi, Noriko @@aut@@ Nakamura, Haruko @@aut@@ Takahashi, Keita @@aut@@ Katsumoto, Atsuko @@aut@@ Tada, Mikiko @@aut@@ Tanaka, Kenichi @@aut@@ Sasaoka, Toshikuni @@aut@@ Miyatake, Satoko @@aut@@ Miyake, Noriko @@aut@@ Saitsu, Hirotomo @@aut@@ Sato, Nozomu @@aut@@ Ozaki, Kokoro @@aut@@ Ohta, Kiyobumi @@aut@@ Yokota, Takanori @@aut@@ Mizusawa, Hidehiro @@aut@@ Mitsui, Jun @@aut@@ Ishiura, Hiroyuki @@aut@@ Yoshimura, Jun @@aut@@ Morishita, Shinichi @@aut@@ Tsuji, Shoji @@aut@@ Takeuchi, Hideyuki @@aut@@ Ishikawa, Kinya @@aut@@ Matsumoto, Naomichi @@aut@@ Ishikawa, Taro @@aut@@ Tanaka, Fumiaki @@aut@@ |
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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 CaV3.1 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 CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. 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|
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Hashiguchi, Shunta |
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Hashiguchi, Shunta ddc 610 bkl 44.90 misc Cerebellum misc Spinocerebellar ataxia 42 misc CACNA1G misc Knock-in mouse misc Purkinje cell misc Inferior olivary nucleus misc Neurodegeneration misc Electrophysiology Ataxic phenotype with altered Ca |
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610 570 DE-600 44.90 bkl Ataxic phenotype with altered Ca Cerebellum Spinocerebellar ataxia 42 CACNA1G Knock-in mouse Purkinje cell Inferior olivary nucleus Neurodegeneration Electrophysiology |
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ddc 610 bkl 44.90 misc Cerebellum misc Spinocerebellar ataxia 42 misc CACNA1G misc Knock-in mouse misc Purkinje cell misc Inferior olivary nucleus misc Neurodegeneration misc Electrophysiology |
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Ataxic phenotype with altered Ca |
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Ataxic phenotype with altered Ca |
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Hashiguchi, Shunta |
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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 |
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ataxic phenotype with altered ca |
| title_auth |
Ataxic phenotype with altered Ca |
| 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 CaV3.1. 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 CaV3.1 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 CaV3.1 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. |
| abstractGer |
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 CaV3.1. 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 CaV3.1 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 CaV3.1 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_unstemmed |
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 CaV3.1. 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 CaV3.1 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 CaV3.1 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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Ataxic phenotype with altered Ca |
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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 |
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|
| score |
7.4012003 |