Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans.
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.
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Yubin
Y
Wang
The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Joshua
J
Hersheson
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Dulce
D
Lopez
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.
Monia
M
Hammer
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Yan
Y
Liu
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Ka-Hung
KH
Lee
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Vanessa
V
Pinto
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Jeff
J
Seinfeld
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.
Sarah
S
Wiethoff
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Jiandong
J
Sun
Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La Rabta, Tunis 1007, Tunisia.
Rim
R
Amouri
Department of Molecular Neurobiology and Neuropathology, National Institute of Neurology, La Rabta, Tunis 1007, Tunisia.
Faycal
F
Hentati
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Neema
N
Baudry
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Jennifer
J
Tran
Laboratory of Neurogenetics, National Institutes of Health, Bethesda 20892, MD, USA.
Andrew B
AB
Singleton
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.
Marie
M
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; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
Alexis
A
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; 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.
Giovanni
G
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; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
Alexandra
A
Durr
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Xiaoning
X
Bi
The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK. Electronic address: h.houlden@ucl.ac.uk.
Henry
H
Houlden
Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA. Electronic address: mbaudry@westernu.edu.
Michel
M
Baudry
D000375:Aging / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002154:Calpain / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002452:Cell Count; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002531:Cerebellum / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018345:Mice, Knockout; D009043:Motor Activity; D009128:Muscle Spasticity / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D009896:Optic Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011689:Purkinje Cells / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009435:Synaptic Transmission
D009687:Nuclear Proteins; D051057:Proto-Oncogene Proteins c-akt; C519282:PHLPP1 protein, mouse; D010749:Phosphoprotein Phosphatases; D002154:Calpain; C484806:CAPN1 protein, human; C112682:Capn1 protein, mouse
apoptosis; ataxia; calpain-1; cerebellum; development