CAPN1

Calpain-1 catalytic subunit (EC 3.4.22.52) (Calcium-activated neutral proteinase 1) (CANP 1) (Calpain mu-type) (Calpain-1 large subunit) (Cell proliferation-inducing gene 30 protein) (Micromolar-calpain) (muCANP) [CANPL1] [PIG30]

Publications

Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.

PubMed

Full text

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.

MeSH Terms

• Aging
• Amino Acid Sequence
• Animals
• Animals, Newborn
• Apoptosis
• Calpain
• Cell Count
• Cerebellar Ataxia
• Cerebellum
• Enzyme Activation
• Female
• Humans
• Intellectual Disability
• Male
• Mice, Knockout
• Motor Activity
• Muscle Spasticity
• Mutation
• Nuclear Proteins
• Optic Atrophy
• Phosphoprotein Phosphatases
• Phosphorylation
• Proto-Oncogene Proteins c-akt
• Purkinje Cells
• Spinocerebellar Ataxias
• Synaptic Transmission

Keywords

• apoptosis
• ataxia
• calpain-1
• cerebellum
• development