Suchergebnisse

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation. ; This study was supported by the ISCIII (FIS PI14/00581) (cofunded by the European Regional Development Fund); 'La Marató de TV3' Foundation 345/C/2014 (to AP, C. Casasnovas, and CP); the Hesperia Foundation and CIBER on Rare Diseases (CIBERER) (ACCI14-759) and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP; the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER) (BFU2015-67400-P) to CP; the Spanish Institute for Health Carlos III (Miguel Servet program CPII16/00016) to SF; CIBERER to NL and MR; and a predoctoral fellowship awarded to DP from the Government of Catalonia through L′Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR; FI-DGR 2014). XJ acknowledges a Sara Borrell postdoctoral fellowship from Instituto de Salud Carlos III.

Historical and social perspectives, together with economic context, are essential to comprehend and appreciate the current status of any discipline. This is particularly true for fields relying on technological advances and with direct effects on society, such as genetics and genomics. ; This study was supported by grants from the Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional(FEDER), Union Europea, una manera de hacer Europa '[FIS PI14/00410], the Autonomous Government of Catalonia [SGR 2014SGR1430] to A.P. The CIBER on Rare Diseases (CIBERER) is an initiative of the ISCIII

Sirtuin 2 (SIRT2) is a member of a family of NAD+ -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal degeneration, which was not present in young SIRT2 mice. In addition, these Sirt2-/- mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between SIRT2 and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for SIRT2 in orchestrating its metabolic regulation. This underscores the value of SIRT2 as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis. ; This study was supported by grants from the Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [FIS PI11/01043, FIS PI14/00410], the Autonomous Government of Catalonia [SGR 2014SGR1430] to A.P., The Spanish Institute for Health Carlos III and 'Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, una manera de hacer Europa' [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F. and the Center for Biomedical Research on Rare Diseases (CIBERER) to M.R., and the Spanish Institute for Health Carlos III and FEDER funds from European Union ('A way to build Europe') [FIS grants PI14/01115, PI13/00584, and PI14/00328], Foundation La Marató de TV3 [345/C/2014], and the Autonomous Government of Catalonia [2014SGR168] to M.J., M.P.O., and R.P. The studies conducted at the Chromatin Biology Laboratory were supported by the Spanish Ministry of Economy and Competitiveness‐MINECO [SAF2011‐25860, SAF2014‐55964R] to A.V.

Animal models are invaluable for biomedical research, especially in the context of rare diseases, which have a very low prevalence and are often complex. Concretely mouse models provide key information on rare disease mechanisms and therapeutic strategies that cannot be obtained by using only alternative methods, and greatly contribute to accelerate the development of new therapeutic options for rare diseases. Despite this, the use of experimental animals remains controversial. The combination of respectful management, ethical laws and transparency regarding animal experimentation contributes to improve society's opinion about biomedical research and positively impacts on research quality, which eventually also benefits patients. Here we present examples of current advances in preclinical research in rare diseases using mouse models, together with our perspective on future directions and challenges. ; This work was supported by a grant from the Center for Biomedical Research on Rare Diseases (CIBERER) (ER18GDT761) to SM-C. Additional support came from: Multi Target and View FEDER/CM-B2017/BMD-3688 and MINECO/FEDER SAF2017-86107-R grants to SM-C and IV-N; CERCA Program/Generalitat de Catalunya, Autonomous Government of Catalonia (2017SGR1206), and CIBERER (ACCI18-27) to AP; Miguel Servet program CPII16/00016 (Instituto de Salud Carlos III co-funded by European Social Fund ESF) to SF; CNIC (ISCIII, Ministerio de Ciencia, Innovación y Universidades), Pro CNIC Foundation, Severo Ochoa Center of Excellence (SEV-2015-0505) to BI and EO; Generalitat de Catalunya (Grups consolidats 2017 SGR 926) to MD. EO was beneficiary of a grant from "Programa de Atracción de Talento" of Comunidad de Madrid (2017-T1/BMD-5185). SM-C holds a ISCiii CIBER postdoctoral researcher contract. The work at CRG was supported by grants from the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya.