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Barneo-Munoz M.,Program in Rare and Genetic Diseases and IBV CSIC Associated Unit | Barneo-Munoz M.,CIBER ISCIII | Juarez P.,Program in Rare and Genetic Diseases and IBV CSIC Associated Unit | Juarez P.,CIBER ISCIII | And 20 more authors.
PLoS Genetics | Year: 2015

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. © 2015 Barneo-Muñoz et al. Source

Hoenicka J.,Program in Rare and Genetic Diseases and IBV CSIC Associated Unit | Hoenicka J.,Research Center Biomedica En Red Of Salud Mental Cibersam | Hoenicka J.,University of Castilla - La Mancha | Garcia-Ruiz P.J.,Fundacion Jimenez Diaz | And 8 more authors.
Neurotoxicity Research | Year: 2015

Impulse control disorders (ICDs) comprise a wide spectrum of abnormal behaviors frequently found in patients with Parkinson’s disease (PD) receiving antiparkinsonian treatment. Some ICDs share several essential features with substance use disorders. In this work, we have studied the addiction-related gene ankyrin repeat and kinase domain containing I (ANKK1) in a sample of PD patients involved in a multicenter study on ICD. We carried out the TaqIA ANKK1 single-nucleotide polymorphism (SNP) genotyping in PD patients. Clinical assessment of ICD was performed using the Questionnaire for impulsive–compulsive disorders in PD. We found no association between TaqIA SNP and ICD in PD patients (p = 0.565). However, when PD patients were grouped according the diagnosis of any ICD with a potentially addictive reinforcement (ICDARs), A1− TaqIA genotype showed significant association (p = 0.036). No association was found for the presence of punding in PD patients (p = 0.289). A logistic regression analysis confirmed the independent effect of the A1− genotype upon ICDARs (OR 8.76, 95 % CI 1.3–57.8, Wald = 5.805, p = 0.024). The TaqIA genotype A1− is associated to ICDAR in our sample and it may differentiate two types of disorders which are part of the ICD definition in PD patients. © 2014, Springer Science+Business Media New York. Source

Pla-Martin D.,Program in Rare and Genetic Diseases and IBV CSIC Associated Unit | Pla-Martin D.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | Calpena E.,Program in Rare and Genetic Diseases and IBV CSIC Associated Unit | Calpena E.,Research Center Biomedica En Red Of Enfermedades Raras Ciberer | And 15 more authors.
Human Molecular Genetics | Year: 2015

Mutations in the GDAP1 gene cause different forms of Charcot-Marie-Tooth (CMT) disease, and the primary clinical expression of this disease is markedly variable in the dominant inheritance form (CMT type 2K; CMT2K), in which carriers of the GDAP1 p.R120W mutation can display a wide range of clinical severity. We investigated the JPH1 gene as a genetic modifier of clinical expression variability because junctophilin-1 (JPH1) is a good positional and functional candidate. We demonstrated that the JPH1-GDAP1 cluster forms a paralogon and is conserved in vertebrates. Moreover, both proteins play a role in Ca2+ homeostasis, and we demonstrated that JPH1 is able to restore the store-operated Ca2+ entry (SOCE) activity in GDAP1-silenced cells. After the mutational screening of JPH1 in a series of 24 CMT2K subjects who harbour the GDAP1 p.R120W mutation, we characterized the JPH1 p.R213P mutation in one patient with a more severe clinical picture. JPH1p.R213P cannot rescue the SOCE response in GDAP1-silenced cells. We observed that JPH1 colocalizes with STIM1, which is the activator of SOCE, in endoplasmic reticulum-plasma membrane puncta structures during Ca2+ release in a GDAP1-dependent manner. However, when GDAP1p.R120W is expressed, JPH1 seems to be retained in mitochondria. We also established that the combination of GDAP1p.R120W and JPH1p.R213P dramatically reduces SOCE activity, mimicking the effect observed in GDAP1 knock-down cells. In summary, we conclude that JPH1 and GDAP1 share a common pathway and depend on each other; therefore, JPH1 can contribute to the phenotypical consequences of GDAP1 mutations. © The Author 2014. Published by Oxford University Press. All rights reserved. Source

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