Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans
Yubin Wang,
Joshua Hersheson,
Dulce Lopez,
Monia Hammer,
Yan Liu,
Ka-Hung Lee,
Vanessa Pinto,
Jeff Seinfeld,
Sarah Wiethoff,
Jiandong Sun,
Rim Amouri,
Faycal Hentati,
Neema Baudry,
Jennifer Tran,
Andrew B. Singleton,
Marie Coutelier,
Alexis Brice,
Giovanni Stevanin,
Alexandra Durr,
Xiaoning Bi,
Henry Houlden,
Michel Baudry
Affiliations
Yubin Wang
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Joshua Hersheson
The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Dulce Lopez
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Monia Hammer
Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La Rabta, Tunis 1007, Tunisia
Yan Liu
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Ka-Hung Lee
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Vanessa Pinto
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
Jeff Seinfeld
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Sarah Wiethoff
The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Jiandong Sun
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
Rim Amouri
Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La Rabta, Tunis 1007, Tunisia
Faycal Hentati
Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La Rabta, Tunis 1007, Tunisia
Neema Baudry
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Jennifer Tran
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
Andrew B. Singleton
Laboratory of Neurogenetics, National Institutes of Health, Bethesda 20892, MD, USA
Marie Coutelier
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, 75013 Paris, France
Alexis Brice
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, 75013 Paris, France
Giovanni Stevanin
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, 75013 Paris, France
Alexandra Durr
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, Université Pierre et Marie Curie Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, 75013 Paris, France
Xiaoning Bi
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
Henry Houlden
The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
Michel Baudry
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA
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.
