title: Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.
abstract: Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain.
authors: Manuela
authors: M
authors: Barneo-Muñoz
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain.
authors: Paula
authors: P
authors: Juárez
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Azahara
authors: A
authors: Civera-Tregón
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Laura
authors: L
authors: Yndriago
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain.
authors: David
authors: D
authors: Pla-Martin
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors: Jennifer
authors: J
authors: Zenker
authors: CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain; Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, Madrid, Spain.
authors: Carmen
authors: C
authors: Cuevas-Martín
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain.
authors: Anna
authors: A
authors: Estela
authors: CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain; Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, Madrid, Spain.
authors: María
authors: M
authors: Sánchez-Aragó
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; Instituto Valenciano de Patología, Catholic University of Valencia, Valencia, Spain.
authors: Jerónimo
authors: J
authors: Forteza-Vila
authors: CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain; Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Universidad Autónoma de Madrid, Madrid, Spain.
authors: José M
authors: JM
authors: Cuezva
authors: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Roman
authors: R
authors: Chrast
authors: Program in Rare and Genetic Diseases and IBV/CSIC Associated Unit, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras (CIBERER), ISCIII, Valencia and Madrid, Spain; University of Castilla-La Mancha School of Medicine at Ciudad Real, Ciudad Real, Spain.
authors: Francesc
authors: F
authors: Palau
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015220:Calcium Channels; C118663:GDAP protein; D009419:Nerve Tissue Proteins