Santiago E. Faraj, Martín E. Noguera, José María Delfino & Javier Santos; Scientific Reportsvolume 9, Article number: 1731 (2019) doi:10.1038/s41598-019-39429-2
Local events that affect specific regions of proteins are of utmost relevance for stability and function. The aim of this study is to quantitatively assess the importance of locally-focused dynamics by means of a simple chemical modification procedure. Taking human Frataxin as a working model, we investigated local fluctuations of the C-terminal region (the last 16 residues of the protein) by means of three L → C replacement mutants: L98C, L200C and L203C. The conformation and thermodynamic stability of each variant was assessed.
Monday, February 11, 2019
Saturday, February 9, 2019
The patient’s view on rare disease trial design – a qualitative study
C. M. W. Gaasterland, M. C. Jansen – van der Weide, M. J. du Prie – Olthof, M. Donk, M. M. Kaatee, R. Kaczmarek, C. Lavery, K. Leeson-Beevers, N. O’Neill, O. Timmis, V. van Nederveen, E. Vroom and J. H. van der Lee; Orphanet Journal of Rare Diseases 2019 14:31 doi:10.1186/s13023-019-1002-z
linical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a ‘classical’ Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients.
linical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a ‘classical’ Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients.
Structural and functional characterization of a frataxin from a thermophilic organism
Rasheed, M. , Jamshidiha, M. , Puglisi, R. , Yan, R. , Cota, E. and Pastore, A. (2019), FEBS J, 286: 495-506. doi:10.1111/febs.14750
Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron–sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron‐binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron–sulfur cluster synthesis, and act as its inhibitor.
Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron–sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron‐binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron–sulfur cluster synthesis, and act as its inhibitor.
Friday, February 1, 2019
Cardiomiòcits de rata com a model d'Atàxia de Friedreich: alteracions cel·lulars i aproximacions terapèutiques
Purroy Lledós, Rosa. Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques, (03-12-2018) Tesis, Director/a: Tamarit Sumalla, Jordi; Ros Salvador, Joaquim
Friedreich Ataxia is an inherited neurodegenerative disease with cardiac alterations and without any effective therapy. It is caused by a decrease of the mitochondrial protein frataxin. Nowadays, the exact function of this protein is still under discussion but it is related to iron homeostasis and oxidative stress. To study the frataxin deficiency consequences we have used a cardiac model based on primary cultures of neonatal rat cardiomyocytess. In this work it has been detected that frataxin deficiency causes i) mitochondrial permeability transition pore (MPTP) alterations, ii) mitochondrial calcium exporter NCLX decrease and iii) activation of calcineurin/NFAT cytosolic pathway that induces hypertrophy. Moreover, oxidative stress has been also studied detecting alterations of the glutathione levels and the redox state of PDH and KGDH mitochondrial complexes. Finally, the use of compounds to revert this phenotype, such as antioxidants or MPTP inhibitors, opens a new therapeutic strategy.
L’Atàxia de Friedreich és una malaltia neurodegenerativa hereditària amb afectació cardíaca per la qual no existeix cap teràpia efectiva. És causada per una disminució de la proteïna mitocondrial frataxina. Actualment, la funció precisa d’aquesta proteïna està en discussió però s’associa amb l’homeòstasi del ferro i l’estrès oxidatiu. Per a estudiar les conseqüències de la manca de frataxina s’ha utilitzat un model cardíac basat en cultius primaris de cardiomiòcits de rates nounades. En aquest treball s’ha detectat que el dèficit de frataxina provoca i) alteració del porus de transició de permeabilitat mitocondrial (MPTP), ii) disminució dels nivells de NCLX, exportador de calci mitocondrial i iii) activació de la via citosòlica calcineurina/NFAT, inductora de la hipertròfia. També s’ha estudiat l’estrès oxidatiu detectant alteracions en els nivells de glutatió i en l’estat redox dels complexos mitocondrials PDH i KGDH. Finalment, la utilització de compostos per revertir aquest fenotip, com antioxidants o inhibidors del MPTP, obren una nova estratègia terapèutica.(CAT)
Friedreich Ataxia is an inherited neurodegenerative disease with cardiac alterations and without any effective therapy. It is caused by a decrease of the mitochondrial protein frataxin. Nowadays, the exact function of this protein is still under discussion but it is related to iron homeostasis and oxidative stress. To study the frataxin deficiency consequences we have used a cardiac model based on primary cultures of neonatal rat cardiomyocytess. In this work it has been detected that frataxin deficiency causes i) mitochondrial permeability transition pore (MPTP) alterations, ii) mitochondrial calcium exporter NCLX decrease and iii) activation of calcineurin/NFAT cytosolic pathway that induces hypertrophy. Moreover, oxidative stress has been also studied detecting alterations of the glutathione levels and the redox state of PDH and KGDH mitochondrial complexes. Finally, the use of compounds to revert this phenotype, such as antioxidants or MPTP inhibitors, opens a new therapeutic strategy.
L’Atàxia de Friedreich és una malaltia neurodegenerativa hereditària amb afectació cardíaca per la qual no existeix cap teràpia efectiva. És causada per una disminució de la proteïna mitocondrial frataxina. Actualment, la funció precisa d’aquesta proteïna està en discussió però s’associa amb l’homeòstasi del ferro i l’estrès oxidatiu. Per a estudiar les conseqüències de la manca de frataxina s’ha utilitzat un model cardíac basat en cultius primaris de cardiomiòcits de rates nounades. En aquest treball s’ha detectat que el dèficit de frataxina provoca i) alteració del porus de transició de permeabilitat mitocondrial (MPTP), ii) disminució dels nivells de NCLX, exportador de calci mitocondrial i iii) activació de la via citosòlica calcineurina/NFAT, inductora de la hipertròfia. També s’ha estudiat l’estrès oxidatiu detectant alteracions en els nivells de glutatió i en l’estat redox dels complexos mitocondrials PDH i KGDH. Finalment, la utilització de compostos per revertir aquest fenotip, com antioxidants o inhibidors del MPTP, obren una nova estratègia terapèutica.(CAT)
Wednesday, January 30, 2019
n $1.9B Alliance, Neurocrine to Develop Voyager Gene Therapies for Parkinson’s, Friedreich’s Ataxia
Neurocrine Biosciences will partner with Voyager Therapeutics to develop and commercialize its gene therapy programs for Parkinson’s disease and Friedreich’s ataxia, plus two other programs to be determined, through a collaboration that could generate more than $1.865 billion for Voyager, the companies said today.
Tuesday, January 29, 2019
Correction to Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich’s Ataxia
Guo L, Wang Q, Weng L, Hauser LA, Strawser CJ, Rocha AG, Dancis A, Mesaros C, Lynch DR, Blair IA. Anal Chem. 2019 Jan 24. doi:10.1021/acs.analchem.9b00141.
New protein biomarker for the Rare Disease Friedreich’s Ataxia.
New protein biomarker for the Rare Disease Friedreich’s Ataxia.
Sunday, January 27, 2019
Patient involvement in medical research: what patients and physicians learn from each other
Kalen Young, Dana Kaminstein, Ana Olivos, Cristina Burroughs, Celeste Castillo-Lee, Joyce Kullman, Carol McAlear, Dianne G. Shaw, Antoine Sreih, George Casey, Vasculitis Patient-Powered Research Network and Peter A. Merkel; Orphanet Journal of Rare Diseases 2019 14:21 doi:10.1186/s13023-018-0969-1
Direct engagement in research design and development by patient-partners and co-learning between investigators and patient-partners can result in a positive and productive working relationship for all members of a medical research team. This bi-directional engagement directly benefits and impacts research design, participant recruitment to studies, and study subject retention.
Direct engagement in research design and development by patient-partners and co-learning between investigators and patient-partners can result in a positive and productive working relationship for all members of a medical research team. This bi-directional engagement directly benefits and impacts research design, participant recruitment to studies, and study subject retention.
Wednesday, January 23, 2019
Rare Diseases Inform Myocardial Phenotypes for Precision Medicine
Macrae, Calum A., Journal of Cardiac Failure , Volume 24 , Issue 10 , 680 - 681
Friedreich's ataxia (FA) is an autosomal recessive “triplet repeat” disorder characterized by cerebellar degeneration, long tract neuropathy, and a generalized myopathy.1 Although neurologic symptoms typically antedate any clinical cardiac involvement, heart failure remains the dominant cause of death in FA. The genetic basis of the disorder is a dramatic expansion of a GAA repeat sequence in the first intron of the FRDA gene, which encodes an iron-binding mitochondrial protein whose function remains incompletely understood.
Friedreich's ataxia (FA) is an autosomal recessive “triplet repeat” disorder characterized by cerebellar degeneration, long tract neuropathy, and a generalized myopathy.1 Although neurologic symptoms typically antedate any clinical cardiac involvement, heart failure remains the dominant cause of death in FA. The genetic basis of the disorder is a dramatic expansion of a GAA repeat sequence in the first intron of the FRDA gene, which encodes an iron-binding mitochondrial protein whose function remains incompletely understood.
Tuesday, January 22, 2019
Modelling of Friedreich’s Ataxia and other Genetic Disorders as Defective / Noisy Genetic Information Processing
SWASTI WAGH, D.K. WAGH; Journal of Ultra Scientist of Physical Sciences - A, Voulume: 30, Issue: 12 DOI:10.22147/jusps-A/301201
Genetic disorders are due to mutation of some gene. For example, Friedreich’s Ataxia is due to mutation of frataxin gene. The mutation causes transmission error (noise) in the transmission channel. In this paper we show how this transmission error can be calculated using information theory approach.
Genetic disorders are due to mutation of some gene. For example, Friedreich’s Ataxia is due to mutation of frataxin gene. The mutation causes transmission error (noise) in the transmission channel. In this paper we show how this transmission error can be calculated using information theory approach.
Friday, January 18, 2019
Heart disease in Friedreich’s ataxia
Hanson E, Sheldon M, Pacheco B, Alkubeysi M, Raizada V.; World J Cardiol. Jan 26, 2019; 11(1): 1-12 Published online Jan 26, 2019. doi: 10.4330/wjc.v11.i1.1
The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in Friedreich’s Ataxia, and introduces gene-targeted and pathology-specific therapies, in addition to the screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in Friedreich’s Ataxia, and introduces gene-targeted and pathology-specific therapies, in addition to the screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.
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