Patel, M., Isaacs, C. J., Seyer, L., Brigatti, K., Gelbard, S., Strawser, C., Foerster, D., Shinnick, J., Schadt, K., Yiu, E. M., Delatycki, M. B., Perlman, S., Wilmot, G. R., Zesiewicz, T., Mathews, K., Gomez, C. M., Yoon, G., Subramony, S. H., Brocht, A., Farmer, J. and Lynch, D. R. (2016), Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.332
Open access article (Creative Commons Attribution-NonCommercial-NoDerivs License)
Objective: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.
Tuesday, July 26, 2016
Monday, July 25, 2016
Non-coding RNAs as drug targets
Masayuki Matsui & David R. Corey, Nature Reviews Drug Discovery (2016), doi:10.1038/nrd.2016.117
The ability of ncRNAs to control gene expression makes them potential targets for drug development. However, the drug discovery process is never easy. Uncertainty about how ncRNAs function (and even whether they have a function) makes lead identification and development even more challenging.
Expanded repeats within introns, 3ʹ untranslated regions (UTRs) or 5ʹ UTRs can produce toxic mutant RNAs (for example, as seen in myotonic dystrophy) or affect the production of proteins (for example, as seen in Friedreich ataxia and Fragile X syndrome).
Case study: Friedreich ataxia.Our laboratory has targeted steric-block locked nucleic acid (LNA) ASOs and duplex RNAs to the expanded GAA repeat in cells derived from patients with Friedreich ataxia. These compounds reduce R‑loop formation and increase frataxin mRNA and protein levels to those found in wild-type cells.
The ability of ncRNAs to control gene expression makes them potential targets for drug development. However, the drug discovery process is never easy. Uncertainty about how ncRNAs function (and even whether they have a function) makes lead identification and development even more challenging.
Expanded repeats within introns, 3ʹ untranslated regions (UTRs) or 5ʹ UTRs can produce toxic mutant RNAs (for example, as seen in myotonic dystrophy) or affect the production of proteins (for example, as seen in Friedreich ataxia and Fragile X syndrome).
Case study: Friedreich ataxia.Our laboratory has targeted steric-block locked nucleic acid (LNA) ASOs and duplex RNAs to the expanded GAA repeat in cells derived from patients with Friedreich ataxia. These compounds reduce R‑loop formation and increase frataxin mRNA and protein levels to those found in wild-type cells.
Sunday, July 24, 2016
A Study to Characterize the Cardiac Phenotype of Individuals With Friedreich's Ataxia (CARFA Study)
ClinicalTrials.gov Identifier: NCT02840669, First received: July 19, 2016
Locations: Hôpital Pitié-Salpêtrière, Paris, France, Sponsors and Collaborators: Annapurna Therapeutics, Adverum Biotechnologies & Weill Medical College of Cornell University
This study is designed to characterize the cardiac manifestations of FA using cardiac magnetic resonance (CMR), echocardiography, serum cardiac biomarkers and evaluation of fatigue severity, in the context of the neurological disease.
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Locations: Hôpital Pitié-Salpêtrière, Paris, France, Sponsors and Collaborators: Annapurna Therapeutics, Adverum Biotechnologies & Weill Medical College of Cornell University
This study is designed to characterize the cardiac manifestations of FA using cardiac magnetic resonance (CMR), echocardiography, serum cardiac biomarkers and evaluation of fatigue severity, in the context of the neurological disease.
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Friday, July 22, 2016
Labile Low-Molecular-Mass Metal Complexes in Mitochondria: Trials and Tribulations of a Burgeoning Field
Paul A. Lindahl and Michael J. Moore, Biochemistry, Article ASAP, DOI: 10.1021/acs.biochem.6b00216, Publication Date (Web): July 19, 2016
Iron, copper, zinc, manganese, cobalt, and molybdenum play important roles in mitochondrial biochemistry, serving to help catalyze reactions in numerous metalloenzymes.
The iron transported through the high-affinity importers mitoferrin 1 and 2 (or Mrs3/4) is ultimately utilized in the biosynthesis of ISC and heme cofactors. Indeed, the majority of Fe that accumulates in mitochondria of frataxin-deficient cells passes through these carrier proteins.
FeIII nanoparticles accumulate in the mitochondria of yeast cells lacking the frataxin homologue (Yfh1), which also contain deficient amounts of ISCs and hemes. What is less commonly realized is that Zn-protoporphyrin IX accumulates in mitochondria from this same strain. Curiously, excess ZnSO4 in the medium prevents the accumulation of Fe in mitochondria of Δyfh1 cells, increases the growth rate of this strain, and mitigates ROS damage. Surprisingly, these responses are not caused by an increase in ISC or heme synthesis, which makes them difficult to explain.
Iron, copper, zinc, manganese, cobalt, and molybdenum play important roles in mitochondrial biochemistry, serving to help catalyze reactions in numerous metalloenzymes.
The iron transported through the high-affinity importers mitoferrin 1 and 2 (or Mrs3/4) is ultimately utilized in the biosynthesis of ISC and heme cofactors. Indeed, the majority of Fe that accumulates in mitochondria of frataxin-deficient cells passes through these carrier proteins.
FeIII nanoparticles accumulate in the mitochondria of yeast cells lacking the frataxin homologue (Yfh1), which also contain deficient amounts of ISCs and hemes. What is less commonly realized is that Zn-protoporphyrin IX accumulates in mitochondria from this same strain. Curiously, excess ZnSO4 in the medium prevents the accumulation of Fe in mitochondria of Δyfh1 cells, increases the growth rate of this strain, and mitigates ROS damage. Surprisingly, these responses are not caused by an increase in ISC or heme synthesis, which makes them difficult to explain.
Thursday, July 21, 2016
Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease
Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Juan Botas, María Dolores Moltó. PLoS ONE 11(7): e0159209. doi:10.1371/journal.pone.0159209
Open Access (Creative Commons Attribution License)
We report several novel genetic modifiers of eye morphology and motor dysfunction in the FRDA fly model. These data provide further support for the notion that disruptions in metal homeostasis may be a primary contributor to FRDA disease pathogenesis.
Open Access (Creative Commons Attribution License)
We report several novel genetic modifiers of eye morphology and motor dysfunction in the FRDA fly model. These data provide further support for the notion that disruptions in metal homeostasis may be a primary contributor to FRDA disease pathogenesis.
Wednesday, July 20, 2016
Crystal Structure of Bacillus subtilis Cysteine Desulfurase SufS and Its Dynamic Interaction with Frataxin and Scaffold Protein SufU
Blauenburg B, Mielcarek A, Altegoer F, Fage CD, Linne U, Bange G, Mohamed A. Marahiel. PLoS ONE 11(7): e0158749. doi:10.1371/journal.pone.0158749
Open access (article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited).
Open access (article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited).
Tuesday, July 19, 2016
Frenkel: one of the forerunners of neurorehabilitation? / Frenkel: ¿un precursor de la neurorrehabilitación?
Cano-de-la-Cuerda R, Rev Neurol. 2016 Jul 16;63(2):79-84.
[Article in Spanish]
Neurorehabilitation is understood as the process intended to reduce the deficiency, limitation of activity and restriction of participation experienced by people as a result of a neurological diseases, and where the professionals involved in this field will aim to reduce the functional involvement degree of the patient.
[Article in Spanish]
Neurorehabilitation is understood as the process intended to reduce the deficiency, limitation of activity and restriction of participation experienced by people as a result of a neurological diseases, and where the professionals involved in this field will aim to reduce the functional involvement degree of the patient.
Sunday, July 17, 2016
Cerebellar Dysfunction and Ataxia in Patients with Epilepsy: Coincidence, Consequence, or Cause?
Filip P, Bareš M, Brázdil M.; Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8KH0NBT
Open-access (article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License.)
Other spinocerebellar ataxias might also be accompanied by epilepsy, although this is probably a coincidence. There was a case report of mesiotemporal epilepsy in an SCA13 patient and one of nocturnal frontal lobe epilepsy in an SCA17 patient. There was also a description of epilepsy in patients with Friedreich ataxia. A list of all possible conditions exceeds the scope of this article.
Open-access (article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License.)
Other spinocerebellar ataxias might also be accompanied by epilepsy, although this is probably a coincidence. There was a case report of mesiotemporal epilepsy in an SCA13 patient and one of nocturnal frontal lobe epilepsy in an SCA17 patient. There was also a description of epilepsy in patients with Friedreich ataxia. A list of all possible conditions exceeds the scope of this article.
Saturday, July 16, 2016
Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells
Jeannine Gerhardt, Angela D. Bhalla, Jill Sergesketter Butler, James W. Puckett, Peter B. Dervan, Zev Rosenwaks, Marek Napierala, Cell Reports, Available online 14 July 2016, ISSN 2211-1247, doi:10.1016/j.celrep.2016.06.075.
Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3′-5′ progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases.
Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3′-5′ progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases.
Thursday, July 14, 2016
Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy
Nishimura Yuhei, Sasagawa Shota, Okabe Shiko, Murakami Soichiro, Ashikawa Yoshifumi, Yuge Mizuki, Kawaguchi Koki, Kawase Reiko, Okamoto Ryuji, Ito Masaaki, TANAKA TOSHIO; Front. Pharmacol., 14 June 2016, doi:10.3389/fphar.2016.00162
Open-access (article distributed under the terms of the Creative Commons Attribution License).
HCM has multiple etiologies, including mutation in sarcomeric genes such as myosin heavy chain 7 (MYH7) and tropomyosin 1 (TPM1) and in non-sarcomeric genes such as PLN and FXN.Haploinsufficiency of FXN is a major cause of FA. FA is associated with progressive HCM, and this is a common cause of death in FA patients. FXN is an iron-binding protein targeted to the mitochondrial matrix, and consistent with this, mitochondrial function is impaired in FA. Comparative transcriptomics could represent a new frontier in the search for novel biomarkers and/or therapeutic targets in diseases with multiple etiologies because it facilitates the identification of dysregulated genes common to all disease etiologie. We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 (Gstk1) was the only gene downregulated. We demonstrate here that knockout of gstk1 in zebrafish increased the expression of HCM marker genes and decreased the cardiac EDV and, to a lesser extent, the ESV, suggesting that downregulation of GSTK1 may be a common mechanism underlying HCM of various etiologies.
Open-access (article distributed under the terms of the Creative Commons Attribution License).
HCM has multiple etiologies, including mutation in sarcomeric genes such as myosin heavy chain 7 (MYH7) and tropomyosin 1 (TPM1) and in non-sarcomeric genes such as PLN and FXN.Haploinsufficiency of FXN is a major cause of FA. FA is associated with progressive HCM, and this is a common cause of death in FA patients. FXN is an iron-binding protein targeted to the mitochondrial matrix, and consistent with this, mitochondrial function is impaired in FA. Comparative transcriptomics could represent a new frontier in the search for novel biomarkers and/or therapeutic targets in diseases with multiple etiologies because it facilitates the identification of dysregulated genes common to all disease etiologie. We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 (Gstk1) was the only gene downregulated. We demonstrate here that knockout of gstk1 in zebrafish increased the expression of HCM marker genes and decreased the cardiac EDV and, to a lesser extent, the ESV, suggesting that downregulation of GSTK1 may be a common mechanism underlying HCM of various etiologies.
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