Olivier Reelfs, Vincenzo Abbate, Agostino Cilibrizzi, Mark A. Pook, Robert C. Hider and Charareh Pourzan;DOI:10.1039/C8MT00257F
Our results reveal a link between FRDA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. Our findings suggest that the high levels of mitochondrial LI in FRDA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage. This study may have implications not only for FRDA but also for other diseases of mitochondrial iron overload, with the view to develop topical mitochondria-targeted iron chelators as skin photoprotective agents.
Wednesday, February 20, 2019
Sunday, February 17, 2019
Pattern of Cerebellar Atrophy in Friedreich’s Ataxia—Using the SUIT Template
Tobias Lindig, Benjamin Bender, Vinod J. Kumar, Till-Karsten Hauser, Wolfgang Grodd, Bettina Brendel, Jennifer Just, Matthis Synofzik, Uwe Klose, Klaus Scheffler, Ulrike Ernemann, Ludger Schöls; Cerebellum (2019). doi:10.1007/s12311-019-1008-z
Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich’s ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich’s ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls.
Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich’s ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich’s ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls.
Friday, February 15, 2019
Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich’s Ataxia Mouse Model
Belén Mollá, Diana C. Muñoz-Lasso, Pablo Calap, Angel Fernandez-Vilata, María de la Iglesia-Vaya, Federico V. Pallardó, Maria Dolores Moltó, Francesc Palau, Pilar Gonzalez-Cabo; Neurotherapeutics (2019). doi:10.1007/s13311-018-00706-z
Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons in YG8R mice. Our findings indicate that PDE inhibitors may become a future FRDA pharmacological treatment.
Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons in YG8R mice. Our findings indicate that PDE inhibitors may become a future FRDA pharmacological treatment.
Wednesday, February 13, 2019
Fly screens for FA
Ellen P. Neff. Dis. Model Mech.11, dmm033811 (2018) doi:10.1038/s41684-018-0143-3
Friedreich’s ataxia (FA) is a degenerative disorder caused by mutations to the mitochondrial protein frataxin. Muscles, including those of the heart, waste over time, and cardiomyopathy is the leading cause of death. Researchers at Universite Paris Diderot previously described a frataxin-deficient Drosophila line that models FA cardiomyopathies. In their latest paper, they use their fly model to screen 1280 drugs that have been approved for use in humans.
Some drugs made things worse—five were toxic—but eleven improved cardiac function in the flies; most effective was the chemotherapy drug paclitaxel. Paclitaxel stabilizes microtubules; in the heart, these cytoskeletal fibers contribute to proper cardiac function. The drug can be toxic so the authors don’t recommend it for therapeutic use, but they suggest that its efficacy indicates a novel mechanism to investigate further.
Friedreich’s ataxia (FA) is a degenerative disorder caused by mutations to the mitochondrial protein frataxin. Muscles, including those of the heart, waste over time, and cardiomyopathy is the leading cause of death. Researchers at Universite Paris Diderot previously described a frataxin-deficient Drosophila line that models FA cardiomyopathies. In their latest paper, they use their fly model to screen 1280 drugs that have been approved for use in humans.
Some drugs made things worse—five were toxic—but eleven improved cardiac function in the flies; most effective was the chemotherapy drug paclitaxel. Paclitaxel stabilizes microtubules; in the heart, these cytoskeletal fibers contribute to proper cardiac function. The drug can be toxic so the authors don’t recommend it for therapeutic use, but they suggest that its efficacy indicates a novel mechanism to investigate further.
Monday, February 11, 2019
Global Implications of Local Unfolding Phenomena, Probed by Cysteine Reactivity in Human Frataxin
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.
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.
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.
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