Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.
Cell Reports. 2016-06-01; 16(1): 79-91
DOI: 10.1016/j.celrep.2016.05.044
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1. Cell Rep. 2016 Jun 28;16(1):79-91. doi: 10.1016/j.celrep.2016.05.044. Epub 2016
Jun 16.
Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and
Cerebellar Ataxia in Mice and Humans.
Wang Y(1), Hersheson J(2), Lopez D(1), Hammer M(3), Liu Y(1), Lee KH(1), Pinto
V(4), Seinfeld J(1), Wiethoff S(5), Sun J(4), Amouri R(6), Hentati F(6), Baudry
N(1), Tran J(1), Singleton AB(7), Coutelier M(8), Brice A(9), Stevanin G(10),
Durr A(9), Bi X(4), Houlden H(11), Baudry M(12).
Author information:
(1)Graduate College of Biomedical Sciences, Western University of Health
Sciences, Pomona, CA 91766, USA.
(2)The National Hospital for Neurology and Neurosurgery and UCL Institute of
Neurology, Queen Square, London WC1N 3BG, UK.
(3)Department of Molecular Neurobiology and Neuropathology, National Institute of
Neurology, La Rabta, Tunis 1007, Tunisia; Laboratory of Neurogenetics, National
Institutes of Health, Bethesda 20892, MD, USA.
(4)College of Osteopathic Medicine of the Pacific, Western University of Health
Sciences, Pomona, CA 91766, USA.
(5)The National Hospital for Neurology and Neurosurgery and UCL Institute of
Neurology, Queen Square, London WC1N 3BG, UK; Center for Neurology and Hertie
Institute for Clinical Brain Research, Eberhard-Karls-University, 72076 Tübingen,
Germany.
(6)Department of Molecular Neurobiology and Neuropathology, National Institute of
Neurology, La Rabta, Tunis 1007, Tunisia.
(7)Laboratory of Neurogenetics, National Institutes of Health, Bethesda 20892,
MD, USA.
(8)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; Laboratory of Human Molecular Genetics, de Duve Institute,
Université Catholique de Louvain, 1200 Brussels, Belgium; Ecole Pratique des
Hautes Etudes (EPHE), Paris Sciences et Lettres (PSL) Research University, 75013
Paris, France.
(9)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; Centre de Référence de Neurogénétique, Hôpital de la
Pitié-Salpêtrière, Assistance Publique – Hôpitaux de Paris, 75013 Paris, France.
(10)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; Ecole Pratique des Hautes Etudes (EPHE), Paris Sciences et
Lettres (PSL) Research University, 75013 Paris, France; Centre de Référence de
Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique – Hôpitaux
de Paris, 75013 Paris, France.
(11)The National Hospital for Neurology and Neurosurgery and UCL Institute of
Neurology, Queen Square, London WC1N 3BG, UK. Electronic address:
.
(12)Graduate College of Biomedical Sciences, Western University of Health
Sciences, Pomona, CA 91766, USA. Electronic address: .
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.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2016.05.044
PMCID: PMC4927383
PMID: 27320912 [Indexed for MEDLINE]