Journal
NEUROBIOLOGY OF DISEASE
Volume 130, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.104516
Keywords
Cerebellum; Spinocerebellar ataxia 42; CACNA1G; Knock-in mouse; Purkinje cell; Inferior olivary nucleus; Neurodegeneration; Electrophysiology
Categories
Funding
- Japan Society for the Promotion of Science [15 K09344, 18 K07503, 17 K07064, 18 K06529, JP17K10080, JP16H05357, P17H01539, 17 K16128, 26780411]
- AMED [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18kk020500]
- Health and Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare, Japan [201711060A]
- Brain Research Institute, Niigata University [2914]
- Takeda Science Foundation
- Wakaba Research Fund (Research Fund for Potential Young Researchers) of Yokohama Foundation for Advanced Medical Science
- Jikei University Research Fund
- Yokohama City University [SK2804]
- Grants-in-Aid for Scientific Research [26780411] Funding Source: KAKEN
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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(v)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(v)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(v)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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