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Lack of GDAP1 Induces Neuronal Calcium and Mitochondrial Defects in a Knockout Mouse Model of Charcot-Marie-Tooth Neuropathy

AutorBarneo-Munoz, Manuela; Juárez, Paula ; Civera-Tregón, Azahara; Yndriago, Laura; Pla-Martín, David ; Zenker, Jennifer; Cuevas-Martín, Carmen ; Estela, Anna ; Sánchez-Aragó, María ; Forteza-Vila, Jerónimo; Cuezva, José M; Chrast, Roman; Palau Martínez, Francesc
Fecha de publicación10-abr-2015
EditorPublic Library of Science
CitaciónPLoS Genetics 11(4):e1005115. (2015)
ResumenMutations 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.
Descripción27 páginas, 9 figuras.
Versión del editorhttp://dx.doi.org/10.1371/journal.pgen.1005115
URIhttp://hdl.handle.net/10261/113828
DOI10.1371/journal.pgen.1005115
ISSN1553-7390
E-ISSN1553-7404
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