期刊
CELL REPORTS
卷 16, 期 1, 页码 79-91出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.044
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资金
- NINDS [P01NS045260-01]
- Medical Research Council UK
- Brain Research Trust
- Wellcome Trust
- NIHR UCL/UCLH BRC
- Agence Nationale de la Recherche (ANR)
- Verum Foundation
- patient association Connaitre les Syndromes Cerebelleux
- Roger de Spoelberg Foundation
- European Union
- program Investissements d'avenir [ANR-10-IAIHU-06]
- Western University of Health Sciences
- Daljit and Elaine Sarkaria Chair
- Fond National de la Recherche Scientifique (aspirant FNRS)
- Brain Research UK [UCCHoulden] Funding Source: researchfish
- Medical Research Council [G0802760, G108/638, G1001253, MR/J004758/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10082] Funding Source: researchfish
- MRC [G108/638, G1001253, MR/J004758/1, G0802760] Funding Source: UKRI
A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.
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