@article {774, title = {Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response.}, journal = {Cell Death Discov}, volume = {9}, year = {2023}, month = {2023 Jul 01}, pages = {217}, abstract = {

Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1 motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1 iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

}, issn = {2058-7716}, doi = {10.1038/s41420-023-01531-w}, author = {Le{\'o}n, Marian and Prieto, Javier and Molina-Navarro, Mar{\'\i}a Micaela and Garcia-Garcia, Francisco and Barneo-Mu{\~n}oz, Manuela and Ponsoda, Xavier and S{\'a}ez, Rosana and Palau, Francesc and Dopazo, Joaquin and Izpisua Belmonte, Juan Carlos and Torres, Josema} } @article {750, title = {CIBERER: Spanish National Network for Research on Rare Diseases: a highly productive collaborative initiative.}, journal = {Clin Genet}, year = {2022}, month = {2022 Jan 20}, abstract = {

CIBER (Center for Biomedical Network Research; Centro de Investigaci{\'o}n Biom{\'e}dica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on Rare Diseases currently consists of 75 research groups belonging to universities, research centers and hospitals of the entire country. CIBERER{\textquoteright}s mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical and cellular research of rare diseases. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this paper, we intend to review CIBERER{\textquoteright}s 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions towards the discovery of new therapies and novel genes associated to diseases, cooperation with patients{\textquoteright} associations and many other topics related to rare disease research. This article is protected by copyright. All rights reserved.

}, issn = {1399-0004}, doi = {10.1111/cge.14113}, author = {Luque, Juan and Mendes, Ingrid and G{\'o}mez, Beatriz and Morte, Beatriz and de Heredia, Miguel L{\'o}pez and Herreras, Enrique and Corrochano, Virginia and Bueren, Juan and Gallano, Pia and Artuch, Rafael and Fillat, Cristina and P{\'e}rez-Jurado, Luis A and Montoliu, Lluis and Carracedo, {\'A}ngel and Mill{\'a}n, Jos{\'e} M and Webb, Susan M and Palau, Francesc and Lapunzina, Pablo} } @article {436, title = {Dysfunctional mitochondrial fission impairs cell reprogramming.}, journal = {Cell Cycle}, volume = {15}, year = {2016}, month = {2016 Dec}, pages = {3240-3250}, abstract = {

We have recently shown that mitochondrial fission is induced early in reprogramming in a Drp1-dependent manner; however, the identity of the factors controlling Drp1 recruitment to mitochondria was unexplored. To investigate this, we used a panel of RNAi targeting factors involved in the regulation of mitochondrial dynamics and we observed that MiD51, Gdap1 and, to a lesser extent, Mff were found to play key roles in this process. Cells derived from Gdap1-null mice were used to further explore the role of this factor in cell reprogramming. Microarray data revealed a prominent down-regulation of cell cycle pathways in Gdap1-null cells early in reprogramming and cell cycle profiling uncovered a G2/M growth arrest in Gdap1-null cells undergoing reprogramming. High-Content analysis showed that this growth arrest was DNA damage-independent. We propose that lack of efficient mitochondrial fission impairs cell reprogramming by interfering with cell cycle progression in a DNA damage-independent manner.

}, keywords = {Animals, Cell Cycle Checkpoints, Cellular Reprogramming, DNA Damage, G2 Phase, Gene Knockdown Techniques, Mice, Mitochondrial Dynamics, Mitosis, Nerve Tissue Proteins, Pluripotent Stem Cells, Transcription Factors}, issn = {1551-4005}, doi = {10.1080/15384101.2016.1241930}, author = {Prieto, Javier and Le{\'o}n, Marian and Ponsoda, Xavier and Garcia-Garcia, Francisco and Bort, Roque and Serna, Eva and Barneo-Mu{\~n}oz, Manuela and Palau, Francesc and Dopazo, Joaquin and L{\'o}pez-Garc{\'\i}a, Carlos and Torres, Josema} } @article {449, title = {Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.}, journal = {Brain}, volume = {139}, year = {2016}, month = {2016 Jan}, pages = {62-72}, abstract = {

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

}, keywords = {Adult, Aged, Animals, Axons, Charcot-Marie-Tooth Disease, Female, gene expression, Humans, Infant, Male, Mice, Middle Aged, mutation, Pedigree, Phenotype, Sciatic Nerve, Sural Nerve, Transcription Factors, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awv311}, author = {Sevilla, Teresa and Lupo, Vincenzo and Mart{\'\i}nez-Rubio, Dolores and Sancho, Paula and Sivera, Rafael and Chumillas, Mar{\'\i}a J and Garc{\'\i}a-Romero, Mar and Pascual-Pascual, Samuel I and Muelas, Nuria and Dopazo, Joaquin and V{\'\i}lchez, Juan J and Palau, Francesc and Espin{\'o}s, Carmen} }