Calpain‐1 Knockout in Mice Causes Degeneration of Cerebellar Granule Cells and Ataxia

Abstract

Abnormal apoptosis is one of the hallmarks of human neurodegenerative disorders, such as spinocerebellar ataxia (SCA), an inherited disease with progressive deterioration of gait and balance, associated with neuronal loss in cerebellum. A recent study reported that SCA in the Parson Russell Terrier dog breed was associated with a calpain‐1 null mutation. Contrary to the established view that overactivation of calpains, a family of calcium‐dependent proteases, leads to neurodegeneration, recent results have shown that synaptic N‐methyl‐D‐aspartate receptor (NMDAR)‐mediated calpain‐1 activation produces neuroprotection via degradation of PH domain and Leucine rich repeat protein phosphatase 1 (PHLPP1), and stimulation of the pro‐survival Protein Kinase B (Akt). Here, we report that the number of apoptotic neurons in various brain structures, including cerebellum, is higher in calpain‐1 knock out (CAPN1 KO) mice, as compared to wild‐type (wt) mice during the postnatal period (P7‐P10). Adult CAPN1 KO mice exhibited reduced granule cell density and impaired motor function. PHLPP1 was increased and p‐Akt decreased in cerebellum of CAPN1 KO mice, as compared to wt mice during postnatal development. Systemic injection (P1‐P7) of Bisperoxo Oxovanadate Dipotassium (BPV), an indirect activator of Akt, as well as crossing CAPN1 KO mice with PHLPP1 KO mice, rescued Akt activation, reduced apoptosis in the developing cerebellum, resulting in increased granule cell survival and improvement of motor function in adult mice. These findings further support the notion that CAPN1 is neuroprotective and suggests that it is a new candidate gene for ataxia.Funded by NINDS grant P0INS045260‐01.