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World Rare Disease Day

February 28th, World Rare Disease Day.

Drs. Ricardo Escalante and Oliver Vincent. Laboratory for the study of the molecular mechanisms of autophagy

Autophagy is an intracellular degradation mechanism essential for cellular homeostasis, differentiation and development. Recent research has highlighted the impact of autophagy in neurodegenerative diseases and aging. Our laboratories use different model systems including the yeast Saccharomyces cerevisiae, the social amoeba Dictyostelium discoideum and mammalian cells in culture to understand the molecular mechanisms of two rare neurodegenerative diseases: chorea-acanthocytosis (ChAc) and Beta-propeller protein-associated neurodegeneration (BPAN), in which autophagy dysfunction may play a relevant role. These diseases are devastating and incurable leading to neurodegeneration with severe movement, psychiatric dysfunction and premature death. VPS13A and WIPI4 (WDR45) are the genes mutated in these diseases, respectively. Understanding the molecular function of VPS13A and WIPI4 is essential for the design of possible treatments.

Lab web:

Dr. Miguel Ángel Fernández Moreno. Physiopathology of the mitochondrial OXPHOS function.

Mitochondria form the compartment of the cell where the vast majority of the cell's energy is generated. Failures in mitochondrial energy production can cause, depending on their severity, health alterations ranging from a situation of weakness to a devastating syndrome, generally with neuromuscular involvement, which may provoque the death of the patient. One of our laboratory's lines of research is the identification of undescribed genes involved in the correct functioning of mitochondria. Among the group of new genes we have found, we would like to highlight two of them, being both of them involved in the mitocondria specific protein synthesis system. One of them, gatC, is part of the glutamyl-tRNA amidotransferase (GAT) complex, responsible for the synthesis of mt-Gln-tRNAgln. The other gene, c6orf203, interacts with the mitochondrial ribosome and is involved in controlling the entry of mitochondrial tRNAs into the ribosome. We characterized gatC in cultured mouse and human cells, as well as in primary cell cultures from patients suffering severe lactic acidosis and hypertrophic cardiomyopathy, common symptoms in severe mitochondrial pathologies, which caused their death in the first months of life. c6orf203 has recently been characterized in cultured human cells showing that its deletion results in a moderate loss of mitochondrial respiratory capacity, so that we are looking for the presence of mutations in patients with non-severe mitochondrial manifestations such as exercise intolerance, deafness, moderate sensory problems, etc. is being tracked.

Understanding the molecular-genetic mechanisms underlying mitochondrial physiology will allow us to understand the phenotypic manifestations of its pathological alterations and to consider therapeutic approaches.

A.- Mitochondrial network in a HEK293T cerll. The cell emits green fluorescence after transfected with a plasmid expressing the GatC::GFP fusion protein. GatC is part of the mitochondrial glutamyl-tRNA amidotransferase complex. The mitochondrial reticulum in Green and the nucleus in the center can be seen as an unstained void (from our lab). B.- Electron microscopic picture of a section of a mitochondrial network tubule. (from Molecular Biology of the Cell 4th Edition). C.- Electron tomography of a section of a tubule of the mitochondrial network (from The internal structure of mitochondria. PMID: 10871882).


Dr. Francesc García Gonzalo. Laboratory of ciliary signalling mechanisms

Ciliopathies are rare genetic diseases caused by cilia dysfunction. Cilia are microtubule-based, hair-like protrusions of the plasma membrane that can function as either motors or sensors. Most ciliopathies affect primary cilia, which work as cellular antennae sensing optical, mechanical, or chemical signals in a cell type-dependent manner. To function properly, these antennae must first be tuned, i.e. primary cilia must accumulate all the necessary receptors and transducers before they can sense their cognate signals. In our lab, we study the molecular mechanisms whereby cells tune their cilia, and how these tuning mechanisms go awry in ciliopathies like Joubert and Bardet-Biedl syndromes, whose manifestations include cognitive and motor deficits, blindness, kidney cysts, obesity, and polydactyly, among others.

Drs. Ana Guadaño Ferraz and Juan Bernal. Thyroid hormones and central nervous system group.

Our research is focused on the role of thyroid hormones in the development and function of the central nervous system. During the last years we have studied the pathophysiology of the ultra-rare disease known as Allan-Herndon-Dudley syndrome. This syndrome is linked to mutations in MCT8, an essential transporter for thyroid hormones availability to the brain. We have described the first histopathological alterations in patients' brains and we continue characterizing potential therapeutic targets. We also use animal models to test different therapeutic strategies, in collaboration with national and international researchers.

We are strongly involved into increasing the visibility of rare disease research to the society, both in scientific, clinical, and academic forums and for the general public (open meetings in public forums and radio programs) as well as in meetings with patient associations of rare diseases.

Noticia Zamora; Ponencia Zamora; Charla Alcobendas; Yo Investigo Yo Soy CSIC

Dr. Isabel Lastres-Becker. New therapeutic strategies in neurodegenerative diseases: Parkinson's disease, tauopathies and amyotrophic lateral sclerosis.

The increase in the half-life of the population leads to greater aging, which is associated with a larger risk of suffering from neurodegenerative diseases. Among the neurodegenerative diseases we can find Parkinson's disease, diseases associated with alterations in the TAU protein (tauopathies) and amyotrophic lateral sclerosis (ALS). All of them are very disabling diseases that currently have no treatment. Therefore, one of the great challenges of our laboratory is to find new therapeutic targets that allow the prevention of neurodegeneration and the search for new drugs to combat them. We collaborate with national groups (CIBERNED), Instituto Teófilo Hernando, and the Hospital de La Paz-IdiPAZ and associations of patients. The image shows stress granules in hippocampal HT22 cells.



Dra. Rosario Perona y Dr. Leandro Sastre. Telomerophaties, diagnosis and treatment. Ciberer group CB06/07/1020

Our group is focused on the molecular diagnosis and therapy of diseases caused by a decrease in telomere length, due to mutations in the genes that control telomerase activity or the structure of telomeres. These diseases known as telomeropathies include those characterized by bone marrow failure such as dyskeratosis congenita, aplastic anemia or hoyeraal-hreidarsson syndrome and, on the other hand, idiopathic or familial pulmonary fibrosis. We have established a facility for the detection and molecular study of telomeropathies at the IIBM, in which we collaborate with many Hospitals of the National Health System, helping with both the diagnosis and the clinical and therapeutic decision-making with telomeropathies patients. We investigate the molecular mechanism associated to the different mutations using different cell models. Finally, we have developed therapeutic tools, based on a GSE4 peptide, for a possible treatment of telomeropathies, focusing on dyskeratosis congenita, ataxia telangiectasia, and pulmonary fibrosis. These studies have been carried out in collaboration with groups from CIBERER (Dr. Juan Bueren and Guillermo Guenechea) and CIBERES (Dra. Maria Molina Molina).

Dr. Victor Ruiz. Human Genetics and Molecular Pathology group. Ciberer group CB06/07/1029

The research activity of our group is focused on the identification of new genes responsible for developmental disorders. In addition, we investigate the corresponding underlying molecular physiopathology with the help of animal and/or cellular disease models, so that we can generate information that can be useful for the innovation of new therapies. In 2020 our group, in collaboration with other national and international labs, has contributed to the identification of 4 new genes mutated in rare diseases: PRKACA, PRKACB, KDELR2 and MAPKAPK5.



Dra. Isabel Varela Nieto. Hearing Neurobiology Group. Ciberer group CB06/07/1021

Our team studies the genetic and molecular bases of human hearing loss. We have contributed the description of new human deafness genes, demonstrated the impact of nutrition and metabolic homeostasis on the progression of deafness, and we are conducting preclinical studies to help improve diagnosis and the development of new treatments such as cholesterolnitrones. We collaborate with national (CIBERER) and international groups and with the ENT service of the Hospital de La Paz-IdiPAZ. We have a strong commitment to outreach to contribute to the prevention of deafness with society in general and with patients, their families and associations. Videos are available by clicking on this link. Join us on March 10th to celebrate the international hearing day

Juan M. Zapata Ph.D.  Preclinical models and new therapies group.

Our research interest involves the study of two rare diseases, chronic lymphocytic leukemia (CLL) and mulibrey nanism (Peerhentupa´s disease).

Chronic lymphocytic leukemia (CLL) is an incurable disease (to know more, click this link). Our group develops murine models of this leukemia to better understand its etiology and evolution and, using these models and cells from CLL patients, we investigate new drugs and treatments that are effective against CLL cells, in particular from patients that have developed resistance to current treatments and are left  without therapeutic options.

In addition, we study the TRIM37 gene. Mutations in this gene are the cause of mulibrey nanism, an extremely rare disease that causes dwarfism and affects the development of multiple organs and systems and currently lacks a cure (to know more, click this link). Our studies focus on the role of TRIM37 in the regulation of the innate immune response and inflammation, using cellular models and a Trim37-deficient murine model developed in our laboratory.

To know more, click these links: Video, entrevista, noticia-rtve, informativos-telecinco.

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