Suchergebnisse

[Background] Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. ; [Methods] A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. ; [Results] WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. ; [Conclusion] This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice. ; This study was supported by the Centre for Biomedical Research on Rare Diseases (CIBERER) (ACCI14-759), the URDCat program (PERIS SLT002/16/00174), the Hesperia Foundation and the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1206) to AP and Instituto de Salud Carlos III (PI14/00581) (cofunded by European Regional Development Fund. ERDF, a way to build Europe) and la Marató de TV3 (345/C/2014) to CC and AP. EV was funded by a grant from the Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811). SF was funded by the Instituto de Salud Carlos III (Miguel Servet programme CPII16/00016, cofunded by European Social Fund. ESF investing in your future) and MR was funded by CIBERER. ; Peer reviewed

The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early-appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3b. We find that GSK-3b inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1 and Abcd1 /Abcd2 / mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross-talk governing energetic and redox homeostasis in XALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK- 3b/NRF2 axis. ; 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" [PFIS FI12/00457] to P.R-R., [FIS PI14/ 01115, FIS PI17/00134] to M.P.O., [FIS PI13/00584, FIS PI14/00328] to R.P., [FIS PI11/01043, FIS PI14/00410, FIS PI17/00916] to A.P., [Miguel Servet program CP11/00080, CPII16/00016, FIS PI15/00857] to S.F.; the European Commission [FP7-241622] to A.P., the European Leukodystrophy Association [ELA2012-033C1] to A.P; the Autonomous Government of Catalonia [SGR 2017SGR696] to R.P. and [SGR 2014SGR1430; 2017SGR1206] to A.P.; and the Centre for Biomedical Research on Rare Diseases (CIBERER) to N.L. and M.R. Locomotor experiments were performed by the SEFALer unit F5 (CIBERER) led by A.P.

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.

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. ; Sí

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.

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.

X-Adrenoleukodystrophy (X-ALD) and its adult-onset, most prevalent variant adrenomyeloneuropathy (AMN) are caused by mutations in the peroxisomal transporter of the very long-chain fatty acid ABCD1. AMN patients classically present spastic paraparesis that can progress over decades, and a satisfactory treatment is currently lacking. Oxidative stress is an early culprit in X-ALD pathogenesis. A combination of antioxidants halts the clinical progression and axonal damage in a murine model of AMN, providing a strong rationale for clinical translation. In this phase II pilot, open-label study, 13 subjects with AMN were administered a high dose of α-tocopherol, N-acetylcysteine, and α-lipoic acid in combination. The primary outcome was the validation of a set of biomarkers for monitoring the biological effects of this and future treatments. Functional clinical scales, the 6-minute walk test (6MWT), electrophysiological studies, and cerebral MRI served as secondary outcomes. Most biomarkers of oxidative damage and inflammation were normalized upon treatment, indicating an interlinked redox and inflammatory homeostasis. Two of the inflammatory markers, MCP1 and 15-HETE, were predictive of the response to treatment. We also observed a significant decrease in central motor conduction time, together with an improvement or stabilization of the 6MWT in 8/10 subjects. This study provides a series of biomarkers that are useful to monitor redox and pro-inflammatory target engagement in future trials, together with candidate biomarkers that may serve for patient stratification and disease progression, which merit replication in future clinical trials. Moreover, the clinical results suggest a positive signal for extending these studies to phase III randomized, placebo-controlled, longer-term trials with the actual identified dose. ClinicalTrials.gov Identifier: NCT01495260. ; This study was funded by grants from the Spanish Ministry of Health, Social Services and Equality (EC10-137), the Spanish Institute Health Carlos III (ICI14/0076) (co-funded by European Regional Development Fund, a way to build Europe), the Hesperia Foundation, the European Commission (Leukotreat FP7-241622), and the Autonomous Government of Catalonia (2014SGR1430; 2017SGR1206) to Aurora Pujol. Montserrat Ruiz was funded by the Center for Biomedical Research on Rare Diseases, an initiative of the Institute of Health Carlos III. Stéphane Fourcade was funded by Miguel Servet Program (CPII16/00016) (co-funded by European Social Fund, investing in your future). Alba Naudí, Manuel Portero-Otín, and Reinald Pamplona have received funding support from the Spanish Ministry of Science and Innovation (BFU2009-11879/BFI).