1. Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans
- Author
-
Joshua Hersheson, Michel Baudry, Alexis Brice, Vanessa Pinto, Jeff Seinfeld, Dulce Lopez, Henry Houlden, Jennifer Tran, Ka-Hung Lee, Marie Coutelier, Monia B. Hammer, Alexandra Durr, Andrew B. Singleton, Fayçal Hentati, Xiaoning Bi, Yan Liu, Sarah Wiethoff, Jiandong Sun, Giovanni Stevanin, Neema Baudry, Yubin Wang, and Rim Amouri
- Subjects
0301 basic medicine ,Male ,Cerebellum ,Aging ,Cell Count ,Synaptic Transmission ,Purkinje Cells ,0302 clinical medicine ,Phosphoprotein Phosphatases ,Phosphorylation ,calpain-1 ,lcsh:QH301-705.5 ,Genetics ,Mice, Knockout ,Calpain ,apoptosis ,Nuclear Proteins ,3. Good health ,Motor coordination ,medicine.anatomical_structure ,Muscle Spasticity ,Spinocerebellar ataxia ,Female ,medicine.symptom ,medicine.medical_specialty ,Ataxia ,Cerebellar Ataxia ,cerebellum ,Biology ,Motor Activity ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Internal medicine ,Intellectual Disability ,medicine ,Animals ,Humans ,Spinocerebellar Ataxias ,Amino Acid Sequence ,Protein kinase B ,development ,Cerebellar ataxia ,ataxia ,Protein phosphatase 1 ,Granule cell ,medicine.disease ,Enzyme Activation ,Optic Atrophy ,030104 developmental biology ,Endocrinology ,Animals, Newborn ,lcsh:Biology (General) ,Mutation ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
SummaryA 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.
- Published
- 2016
- Full Text
- View/download PDF