Wing-Hang Tong, Nunziata Maio, De-Liang Zhang, Erika M. Palmieri, Hayden Ollivierre, Manik C. Ghosh, Daniel W. McVicar and Tracey A. Rouault; Blood Advances 2018 2:1146-1156; doi: doi:10.1182/bloodadvances.2018015669
hese results reveal new regulatory pathways and novel roles of the Fe-S cluster biogenesis machinery in modifying the epigenome and acetylome and provide new insights into the etiology of Fe-S cluster biogenesis disorders.
Interestingly, we showed that silencing of FXN and ISCU resulted in increased MEC17 levels and increased α-tubulin acetylation.
Extensive chromatin immunoprecipitation data collected at the FRDA locus, which contains an expanded trinucleotide repeat (GAA)n in the first intron of FXN, had shown that the levels of the heterochromatin mark H3K9me3 were enriched, whereas the levels of acetylated H3 and H4 were reduced. Our finding that decreased Fe-S cluster biogenesis resulted in decreased overall histone acetylation and increased H3K9me3 levels poses an interesting possibility of a negative feedback mechanism that potentiates a progressive loss of FXN expression in the postmitotic cells that are most severely affected in FRDA. Furthermore, our results showed that silencing of Fe-S cluster biogenesis factors reduced the levels of ELP3, a subunit of the Elongator complex that has roles in growth cone motility and axonal outgrowth. In addition, our studies revealed that silencing of FXN or ISCU induced the α-tubulin acetyltransferase MEC17, resulting in hyperacetylation of α-tubulin. Reversible acetylation of tubulin confers mechanical protection to microtubules51 and controls their interaction with cellular components52 and is critical for neuronal development and function, growth factor or apoptotic signaling, and cell cycle progression. Acetylation of K40 of α-tubulin is mainly controlled by the cytosolic acetyltransferase MEC17 and the cytosolic deacetylases HDAC6 and SIRT2. Notably, a mouse model of FRDA cardiomyopathy with ablation of FXN had increased mitochondrial protein acetylation that was attributed to a decrease in the mitochondrial NAD+/NADH ratio, which can lower the activity of the mitochondrial deacetylase SIRT3. Thus, our findings suggest that the roles of PDHc, ELP3, and MEC17 in the etiology of FRDA, GLRX5-related sideroblastic anemias, and other Fe-S cluster biogenesis disorders warrant further study.
Tuesday, May 29, 2018
Saturday, May 26, 2018
Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich’s ataxia patients
Daniel Nachun, Fuying Gao, Charles Isaacs, Cassandra Strawser, Zhongan Yang, Deepika Dokuru, Victoria Van Berlo, Renee Sears, Jennifer Farmer, Susan Perlman, David R Lynch, Giovanni Coppola; Human Molecular Genetics, ddy198, doi:10.1093/hmg/ddy198
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.
A missed Fe-S cluster handoff causes a metabolic shakeup
Olivier Berteau; The Journal of Biological Chemistry 293, 8312-8313. doi: 10.1074/jbc.H118.002883
these findings hold significance for the biochemical and medical communities because the cellular phenotype induced mirrors pathological conditions encountered, for example, in nonadipose tissues such as heart and liver with possible connections to Friedreich's ataxia, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Further research at the intersection between Fe-S cluster biogenesis and cellular metabolism is thus more than likely to bring unexpected insights into the pathogenesis of poorly understood diseases.
these findings hold significance for the biochemical and medical communities because the cellular phenotype induced mirrors pathological conditions encountered, for example, in nonadipose tissues such as heart and liver with possible connections to Friedreich's ataxia, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Further research at the intersection between Fe-S cluster biogenesis and cellular metabolism is thus more than likely to bring unexpected insights into the pathogenesis of poorly understood diseases.
Acute loss of iron–sulfur clusters results in metabolic reprogramming and generation of lipid droplets in mammalian cells
Daniel R. Crooks, Nunziata Maio§, Andrew N. Lane, Michal Jarnik, Richard M. Higashi, Ronald G. Haller, Ye Yang, Teresa W-M. Fan, W. Marston Linehan and Tracey A. Rouault; The Journal of Biological Chemistry 293, 8297-8311. doi: 10.1074/jbc.RA118.001885
Elucidation of the mechanisms of citrate and lipid droplet accumulation in nonadipose tissues during disease states may reveal important insights into the pathogenesis of a significant number of poorly understood diseases.
Elucidation of the mechanisms of citrate and lipid droplet accumulation in nonadipose tissues during disease states may reveal important insights into the pathogenesis of a significant number of poorly understood diseases.
Friday, May 25, 2018
Improving the analysis of composite endpoints in rare disease trials
Martina McMenami, Anna Berglind and James M. S. Wason; Orphanet Journal of Rare Diseases 201813:81 doi:10.1186/s13023-018-0819-1
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
In rare diseases where there are few or no available treatments and limited opportunity to test emerging new treatments, the power to detect an effective treatment is of critical importance. The augmented binary method with small sample adjustments offers a substantial improvement for trials in these populations over methods currently being used, which throw away valuable information. We recommend the use of the augmented binary method in relevant rare disease trials using composite endpoints and supply R code to assist with the implementation.
Biomimetic Artificial Epigenetic Code for Targeted Acetylation of Histones
Junichi Taniguchi, Yihong Feng, Ganesh N. Pandian, Fumitaka Hashiya, Takuya Hidaka, Kaori Hashiya, Soyoung Park, Toshikazu Bando, Shinji Ito, and Hiroshi Sugiyama; . Am. Chem. Soc., Article ASAP DOI: 10.1021/jacs.8b01518 Publication Date (Web): May 24, 2018
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Recently, Ansari’s group reported a conjugate called Syn-TEF by coupling a PIP with another bromodomain inhibitor(+)-JQ1, selective to the bromodomain and extraterminal(BET) protein family. 45 Syn-TEF1 targeting expanded GAA repeats in the frataxin (FXN) gene successfully recruited BET protein BRD4 (bromodomain 4) to the gene locus in Friedreich’s ataxia (FRDA) patient-derived cells, resulting intranscriptional elongation of FXN. However, Syn-TEF and Bi-PIP target different members of the BD protein family and, therefore, are demonstrated to cause different outcomes; i.e.,while Syn-TEF causes BRD4-dependent transcriptional elongation, Bi-PIP causes P300 dependent histone acetylation. Thus,Bi-PIP and Syn-TEF can be used for different purposes, and this allows us to expand the range of potential applications of the synthetic epigenetic regulators.
Sunday, May 20, 2018
Voyager Therapeutics Announces Additional Data at the American Society of Gene and Cell Therapy 2018 Annual Meeting
CAMBRIDGE, Mass., May 18, 2018 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases today announced additional data presentations at the American Society of Gene and Cell Therapy (ASGCT) taking place May 16-19, 2018, in Chicago, Ill.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Oral Presentation Title: "Rescue of Central and Peripheral Neurological Phenotype in a Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin with a Novel Capsid" Abstract O672.
Data presented at this year's ASGCT meeting demonstrated in a transgenic mouse model of FA, that one-time, post-symptomatic IV dosing of Voyager's vector composed of a novel AAV capsid and a frataxin transgene durably improved motor function and rescued the FA phenotype based on multiple functional tests of sensory and motor behavior.
Thursday, May 17, 2018
Pediatric Ataxia: Focus on Chronic Disorders.
Lynch DR, McCormick A, Schadt K, Kichula E.; Semin Pediatr Neurol. 2018 Apr;25:54-64. doi: 10.1016/j.spen.2018.01.001.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
DNA triplex structure, thermodynamics, and destabilisation: insight from molecular simulations
Belinda J. Boehm, Charles Whidborne, Alexander L. Button, Tara L. Pukala and David M. Huang; Phys Chem Chem Phys. 2018 May 10. doi: 10.1039/c8cp02385a
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
Cardiovascular and sudomotor autonomic assessment in Friedreich’s Ataxia
Karen A. Girotto Takazaki, Alberto Martinez, Thiago Junqueira Rezende, Carelis González-Salazar, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. Franca; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e86
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
Peripheral nerve ultrasound in Friedreich’s ataxia
Eoin Mulroy, Luciana Pelosi, Ruth Leadbetter, Purwa Joshi, Miriam Rodrigues, Stuart Mossman, Dean Kilfoyle, Richard Roxburgh; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e167-e168 doi:10.1016/j.clinph.2018.04.429
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
The dys-regulation of anti-oxidant defense via an impairment of Nrf2 response in the pathology of Friedreich’s ataxia
Shannon Chiang, Amy Anzovino, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang; Free Radical Biology and Medicine, Volume 120, Supplement 1, 20 May 2018, Pages S35 doi:10.1016/j.freeradbiomed.2018.04.120
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
A CRISPR/TALEN-mediated gene editing approach for the Frataxin gene
Silvia Zaccagnino. Edizioni Accademiche Italiane, ISBN: 978-3-330-77664-7
Development and characterization of a new Friedreich Ataxia cellular model
Development and characterization of a new Friedreich Ataxia cellular model
Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia
Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Aurélie Eisenmann, Hélène Puccio, Molecular Therapy , Volume 0 , Issue 0 , DOI: 10.1016/j.ymthe.2018.05.006
Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin positive cells which recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, proprioceptive neurons can survive for many weeks without frataxin, although fully dysfunctional. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue the sensory neuropathy associated with frataxin deficiency, thus establishing the preclinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin positive cells which recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, proprioceptive neurons can survive for many weeks without frataxin, although fully dysfunctional. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue the sensory neuropathy associated with frataxin deficiency, thus establishing the preclinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry
Angeliki Pappa, Martin G. Häusler, Andreas Veigel, Konstantina Tzamouranis, Martin W. Pfeifer, Andreas Schmidt, Martin Bökamp, Holger Haberland, Siegfried Wagner, Joachim Brückel, Gideon de Sousa, Lukas Hackl, Esther Bollow, Reinhard W Holl, Diabetes Res Clin Pract. 2018 May 12. pii: S0168-8227(17)32029-6 DOI: 10.1016/j.diabres.2018.05.008
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
Wednesday, May 16, 2018
The genetic nomenclature of recessive cerebellar ataxias
Rossi, M. , Anheim, M. , Durr, A. , Klein, C. , Koenig, M. , Synofzik, M. , Marras, C. , van de Warrenburg, B. P. and , (2018), Mov Disord.. . doi:10.1002/mds.27415
The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings.
The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings.
Cognitive and functional connectivity alterations in Friedreich's ataxia
Sirio Cocozza, Teresa Costabile, Enrico Tedeschi, Filomena Abate, Camilla Russo, Agnese Liguori, Walter Del Vecchio, Francesca Paciello, Mario Quarantelli, Alessandro Filla, Arturo Brunetti, Francesco Saccà; Annals of Clinical and Translational Neurology doi:10.1002/acn3.555
The aim of this study was to perform the first resting‐state functional MRI (RS‐fMRI) analysis in Friedreich's ataxia (FRDA) patients to assess possible brain functional connectivity (FC) differences in these patients, and test their correlations with neuropsychological performances.
The aim of this study was to perform the first resting‐state functional MRI (RS‐fMRI) analysis in Friedreich's ataxia (FRDA) patients to assess possible brain functional connectivity (FC) differences in these patients, and test their correlations with neuropsychological performances.
EU/3/18/1990: Public summary of opinion on orphan designation: Dimethyl fumarate for the treatment of Friedreich's ataxia
European Medicines Agency. On 21 March 2018, orphan designation (EU/3/18/1990) was granted by the European Commission to PharmaBio Consulting, Germany, for dimethyl fumarate for the treatment of Friedreich's ataxia.
Sunday, May 13, 2018
Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly
Kai Cai, Ronnie O. Frederick, Marco Tonelli, John L. Markley, Journal of Inorganic Biochemistry, Volume 183, 2018, Pages 107-116,
ISSN 0162-0134, doi: 10.1016/j.jinorgbio.2018.03.007.
Frataxin (FXN) binds one Fe2+; the Fe2+-FXN complex is stabilized by its interaction with the scaffold protein (ISCU) on cysteine desulfurase. Upon the addition of reduced ferredoxin (Red-FDX) and l-cysteine, ferredoxin is oxidized (Ox-FDX), l-cysteine is converted to l-alanine generating sulfur, Fe2+ is oxidized to Fe3+, Fe-S binds to ISCU.
ISSN 0162-0134, doi: 10.1016/j.jinorgbio.2018.03.007.
Frataxin (FXN) binds one Fe2+; the Fe2+-FXN complex is stabilized by its interaction with the scaffold protein (ISCU) on cysteine desulfurase. Upon the addition of reduced ferredoxin (Red-FDX) and l-cysteine, ferredoxin is oxidized (Ox-FDX), l-cysteine is converted to l-alanine generating sulfur, Fe2+ is oxidized to Fe3+, Fe-S binds to ISCU.
Saturday, May 12, 2018
Small molecules capable of activating DNA methylation–repressed genes targeted by the p38 mitogen-activated protein kinase pathway
Xiang Li, Erchang Shang, Qiang Dong, Yingfeng Li, Jing Zhang, Shaohua Xu, Zuodong Zhao, Wei Shao, Cong Lv, Yong Zheng, Hailin Wang, Xiaoguang Lei, Bing Zhu and Zhuqiang Zhang; J. Biol. Chem. 2018 293: 7423-7436. doi: 10.1074/jbc.RA117.000757
DNA methylation changes in certain loci can directly cause certain neurological diseases, including fragile X syndrome, Friedreich’s ataxia and spinal muscular atrophy, which can be caused by DNA hypermethylation on the promoter regions of the FMR1, FXN and SMN genes respectively. Thus, small molecules that can activate genes silenced by DNA methylation are of clinical relevance.
DNA methylation changes in certain loci can directly cause certain neurological diseases, including fragile X syndrome, Friedreich’s ataxia and spinal muscular atrophy, which can be caused by DNA hypermethylation on the promoter regions of the FMR1, FXN and SMN genes respectively. Thus, small molecules that can activate genes silenced by DNA methylation are of clinical relevance.
Tuesday, May 8, 2018
Monthly update: April 6-Mai 6, 2018
Monthly
update: April 6-Mai 6, 2018
Emergence of breath testing as a new
non-invasive diagnostic modality for neurodegenerative diseases
Sunday,
April 22, 2018
Sunday, May 6, 2018
Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice
Misa Hirose, Paul Schilf, Yask Gupta, Kim Zarse, Axel Künstner, Anke Fähnrich, Hauke Busch, Junping Yin, Marvin N. Wright, Andreas Ziegler, Marie Vallier, Meriem Belheouane, John F Baines, Diethard Tautz, Kornelia Johann, Rebecca Oelkrug, Jens Mittag, Hendrik Lehnert, Alaa Othman, Olaf Jöhren, Markus Schwaninger, Cornelia Prehn, Jerzy Adamski, Kensuke Shima, Jan Rupp, Robert Häsler, Georg Fuellen, Rüdiger Köhling, Michael Ristow & Saleh M. Ibrahim; Scientific Reports volume 8, Article number: 5872 (2018) doi:10.1038/s41598-018-24290-6
One example of such disorders is Friedreich Ataxia (FA), which is resulted by the impaired expression of the nuclear genome encoded frataxin protein that affect OXPHOS function by mediating mitochondrial iron-sulphur-cluster biosynthesis. FA patients develop diabetes and exhibited decreased lifespan, and experimental evidence using different models showed that a frataxin knock-out cause diabetes in mice, and knocking down of the frataxin gene resulted in shorter lifespan in worms.
One example of such disorders is Friedreich Ataxia (FA), which is resulted by the impaired expression of the nuclear genome encoded frataxin protein that affect OXPHOS function by mediating mitochondrial iron-sulphur-cluster biosynthesis. FA patients develop diabetes and exhibited decreased lifespan, and experimental evidence using different models showed that a frataxin knock-out cause diabetes in mice, and knocking down of the frataxin gene resulted in shorter lifespan in worms.
Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines
Michael R. Pranzatelli, Front Immunol. 2018; 9: 557. Published online 2018 Apr 4. doi:10.3389/fimmu.2018.00557
The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic).
Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.
Interferon-gamma, the sole type 2 IFN, binds to the IFN-γ-R1 and IFN-γ-R2 receptors (also denoted IFNGR1 and R2). IFN-γ-1b is FDA-approved for chronic granulomatous diseases and osteopetrosis. A phase III study (NCT024155127) of IFN-γ-1b for the treatment of Friedreich ataxia has been completed recently, but without study results yet, based on positive results from as phase II study. Treatment with IFN-γ exacerbated MS.
In preclinical studies, administration of G-CSF in a murine model of Friedreich ataxia resulted in clinical improvement and reduction in inflammation and gliosis. IL-10 is such a powerful counteractant of pro-inflammatory cytokines, one would hope there is more progress in this area.
The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic).
Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.
Interferon-gamma, the sole type 2 IFN, binds to the IFN-γ-R1 and IFN-γ-R2 receptors (also denoted IFNGR1 and R2). IFN-γ-1b is FDA-approved for chronic granulomatous diseases and osteopetrosis. A phase III study (NCT024155127) of IFN-γ-1b for the treatment of Friedreich ataxia has been completed recently, but without study results yet, based on positive results from as phase II study. Treatment with IFN-γ exacerbated MS.
In preclinical studies, administration of G-CSF in a murine model of Friedreich ataxia resulted in clinical improvement and reduction in inflammation and gliosis. IL-10 is such a powerful counteractant of pro-inflammatory cytokines, one would hope there is more progress in this area.
Saturday, May 5, 2018
Lipophilic methylene blue analogues enhance mitochondrial function and increase frataxin levels in a cellular model of Friedreich’s Ataxia
Omar M. Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P. Visavadiya, Sidney M. Hecht, Bioorganic & Medicinal Chemistry, Available online 4 May 2018, ISSN 0968-0896, doi:10.1016/j.bmc.2018.05.005.
A series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich’s ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production.
A series of methylene blue analogues has been synthesized and characterized for their in vitro biochemical and biological properties in cultured Friedreich’s ataxia lymphocytes. Favorable methylene blue analogues were shown to increase frataxin levels and mitochondrial biogenesis, and to improve aconitase activity. The analogues were found to be good ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I and from glutathione depletion. The analogues also preserved mitochondrial membrane potential and augmented ATP production.
How Orphan Drugs Became a Highly Profitable Industry
The Scientist; By Diana Kwon | May 1, 2018
Government incentives, advances in technology, and an army of patient advocates have spun a successful market—but abuses of the system and exorbitant prices could cause a backlash.
Government incentives, advances in technology, and an army of patient advocates have spun a successful market—but abuses of the system and exorbitant prices could cause a backlash.
Friday, May 4, 2018
The mystery of the cerebellum: clues from experimental and clinical observations
Charlotte Lawrenson, Martin Bares, Anita Kamondi, Andrea Kovács, Bridget Lumb, Richard Apps, Pavel Filip and Mario Manto; Cerebellum & Ataxias 20185:8 doi:10.1186/s40673-018-0087-9
Its dense connectivity with cerebral cortex, thalamic nuclei, brainstem nuclei and spinal cord, as well as its critically high number of neurons put the cerebellum in a unique position for a participation in cognitive, affective and sensorimotor operations. This special session has highlighted this aspect by taking fear behaviour, motor control, timing contributions and tremor as 4 examples of productive fields of research.
Its dense connectivity with cerebral cortex, thalamic nuclei, brainstem nuclei and spinal cord, as well as its critically high number of neurons put the cerebellum in a unique position for a participation in cognitive, affective and sensorimotor operations. This special session has highlighted this aspect by taking fear behaviour, motor control, timing contributions and tremor as 4 examples of productive fields of research.
Current and Promising Therapies in Autosomal Recessive Ataxias
Vincent Picher-Martel, Nicolas Dupre. CNS Neurol Disord Drug Targets. 2018 Apr 18. doi: 10.2174/1871527317666180419115029. [Epub ahead of print]
The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich’s ataxia, Ataxia-telangiectasia, Wilson’s disease and Niemann-Pick disease in the next few years.
The aim of this review is to provide a comprehensive clinical profile and to review the currently available therapies. We overview the physiopathology, neurological features and diagnostic approach of the common recessive ataxias. The emphasis is also made on potential drugs currently or soon-to-be in clinical trials. For instance, promising gene therapies raise the possibility of treating differently Friedreich’s ataxia, Ataxia-telangiectasia, Wilson’s disease and Niemann-Pick disease in the next few years.
Tuesday, May 1, 2018
Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective
Aaron Sathyanesan, Vittorio Gallo, Neurobiology of Learning and Memory, Available online 30 April 2018, ISSN 1074-7427, doi:10.1016/j.nlm.2018.04.016.
The fact that clinicians do not wait till the infant or child reaches the adult stage to intervene therapeutically and measure behavioral outcomes should prompt neuroscientists to rethink how behavior is typically analyzed in pre-clinical animal models of neurodevelopmental disorders.
One of the behavioral hallmarks of early cerebellar injury or childhood onset genetic ataxia is abnormal gait and postural control. Children affected with diseases such as Friedreich’s Ataxia and Ataxia Telangiectasia display gait deficits due to inter- and intra-limb miscoordination, highlighting the importance of cerebellar circuitry to gait control during development.
The biggest advantage of using the Erasmus Ladder is the integration of measuring locomotor performance such as gait dynamics and coordination, as well as an associative, adaptive, conditioned learning paradigm to study cerebellar function
The fact that clinicians do not wait till the infant or child reaches the adult stage to intervene therapeutically and measure behavioral outcomes should prompt neuroscientists to rethink how behavior is typically analyzed in pre-clinical animal models of neurodevelopmental disorders.
One of the behavioral hallmarks of early cerebellar injury or childhood onset genetic ataxia is abnormal gait and postural control. Children affected with diseases such as Friedreich’s Ataxia and Ataxia Telangiectasia display gait deficits due to inter- and intra-limb miscoordination, highlighting the importance of cerebellar circuitry to gait control during development.
The biggest advantage of using the Erasmus Ladder is the integration of measuring locomotor performance such as gait dynamics and coordination, as well as an associative, adaptive, conditioned learning paradigm to study cerebellar function
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