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https://www.readbyqxmd.com/read/29666341/genetic-testing-for-clinically-suspected-spinocerebellar-ataxias-report-from-a-tertiary-referral-centre-in-india
#1
Sowmya Devatha Venkatesh, Mahesh Kandasamy, Nagaraj S Moily, Radhika Vaidyanathan, Lakshmi Narayanan Kota, Syama Adhikarla, Ravi Yadav, Pramod Kumar Pal, Sanjeev Jain, Meera Purushottam
Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative syndromes, characterized by a wide range of muscular weakness and motor deficits, caused due to cerebellar degeneration. The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA...
March 2018: Journal of Genetics
https://www.readbyqxmd.com/read/29625173/brain-mitochondrial-iron-accumulates-in-huntington-s-disease-mediates-mitochondrial-dysfunction-and-can-be-removed-pharmacologically
#2
Sonal Agrawal, Julia Fox, Baskaran Thyagarajan, Jonathan Fox
Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin...
April 3, 2018: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29623423/clinical-and-genetic-aspects-of-defects-in-the-mitochondrial-iron-sulfur-cluster-synthesis-pathway
#3
REVIEW
A V Vanlander, R Van Coster
Iron-sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron-sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron-sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich's ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported...
April 5, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29610276/the-transcriptional-regulator-ccctc-binding-factor-limits-oxidative-stress-in-endothelial-cells
#4
Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish, Paul Delgado Olguin
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 owing to defective yolk sac and placental vascular development...
April 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29576242/interactions-of-iron-bound-frataxin-with-iscu-and-ferredoxin-on-the-cysteine-desulfurase-complex-leading-to-fe-s-cluster-assembly
#5
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
Frataxin (FXN) is involved in mitochondrial iron‑sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry and multinuclear NMR spectroscopy to investigate interactions among the components of the biological machine that carries out the assembly of iron‑sulfur clusters in human mitochondria. Our results show that FXN tightly binds a single Fe2+ but not Fe3+ ...
March 15, 2018: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29576218/mutations-in-pmpcb-encoding-the-catalytic-subunit-of-the-mitochondrial-presequence-protease-cause-neurodegeneration-in-early-childhood
#6
F-Nora Vögtle, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W Friederich, Susan M White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A Jähn, Oliver Keminer, Katherine L Helbig, Carolyn F Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu, Deepali N Shinde, Ulrich Stephani, Johan L K Van Hove, Franz-Josef Müller, Ingo Helbig
Mitochondrial disorders causing neurodegeneration in childhood are genetically heterogeneous, and the underlying genetic etiology remains unknown in many affected individuals. We identified biallelic variants in PMPCB in individuals of four families including one family with two affected siblings with neurodegeneration and cerebellar atrophy. PMPCB encodes the catalytic subunit of the essential mitochondrial processing protease (MPP), which is required for maturation of the majority of mitochondrial precursor proteins...
March 21, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29572489/iron-regulatory-protein-deficiency-compromises-mitochondrial-function-in-murine-embryonic-fibroblasts
#7
Huihui Li, Hongting Zhao, Shuangying Hao, Longcheng Shang, Jing Wu, Chuanhui Song, Esther G Meyron-Holtz, Tong Qiao, Kuanyu Li
Iron is essential for growth and proliferation of mammalian cells. The maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs) through binding to the cognate iron-responsive elements in target mRNAs and thereby regulating the expression of target genes. Irp1 or Irp2-null mutation is known to reduce the cellular iron level by decreasing transferrin receptor 1 and increasing ferritin. Here, we report that Irp1 or Irp2-null mutation also causes downregulation of frataxin and IscU, two of the core components in the iron-sulfur cluster biogenesis machinery...
March 23, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29568068/identification-of-p38-mapk-as-a-novel-therapeutic-target-for-friedreich-s-ataxia
#8
M Grazia Cotticelli, Shujuan Xia, Avinash Kaur, Daniel Lin, Yongping Wang, Eric Ruff, John W Tobias, Robert B Wilson
Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence...
March 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29563863/mitofusin-dependent-er-stress-triggers-glial-dysfunction-and-nervous-system-degeneration-in-a-drosophila-model-of-friedreich-s-ataxia
#9
Oliver Edenharter, Stephan Schneuwly, Juan A Navarro
Friedreich's ataxia (FRDA) is the most important recessive ataxia in the Caucasian population. It is caused by a deficit of the mitochondrial protein frataxin. Despite its pivotal effect on biosynthesis of iron-sulfur clusters and mitochondrial energy production, little is known about the influence of frataxin depletion on homeostasis of the cellular mitochondrial network. We have carried out a forward genetic screen to analyze genetic interactions between genes controlling mitochondrial homeostasis and Drosophila frataxin...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29555919/frataxin-overexpression-in-m%C3%A3-ller-cells-protects-retinal-ganglion-cells-in-a-mouse-model-of-ischemia-reperfusion-injury-in-vivo
#10
Rowena Schultz, Melanie Krug, Michel Precht, Stefanie G Wohl, Otto W Witte, Christian Schmeer
Müller cells are critical for retinal function and neuronal survival but can become detrimental in response to retinal ischemia and increased oxidative stress. Elevated oxidative stress increases expression of the mitochondrial enzyme frataxin in the retina, and its overexpression is neuroprotective after ischemia. Whether frataxin expression in Müller cells might improve their function and protect neurons after ischemia is unknown. The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo...
March 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29534309/bone-marrow-transplantation-stimulates-neural-repair-in-friedreich-s-ataxia-mice
#11
Kevin C Kemp, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding, Alastair Wilkins
OBJECTIVES: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease. METHODS: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests...
March 13, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29511616/biophysical-characterisation-of-the-recombinant-human-frataxin-precursor
#12
Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini, Javier Santos
Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81-210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1-210). We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29499876/progress-in-the-treatment-of-friedreich-ataxia
#13
REVIEW
Geneieve Tai, Louise A Corben, Eppie M Yiu, Sarah C Milne, Martin B Delatycki
Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways...
February 19, 2018: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/29491838/iron-sulfur-and-molybdenum-cofactor-enzymes-regulate-the-drosophila-life-cycle-by-controlling-cell-metabolism
#14
Zvonimir Marelja, Silke Leimkühler, Fanis Missirlis
Iron sulfur (Fe-S) clusters and the molybdenum cofactor (Moco) are present at enzyme sites, where the active metal facilitates electron transfer. Such enzyme systems are soluble in the mitochondrial matrix, cytosol and nucleus, or embedded in the inner mitochondrial membrane, but virtually absent from the cell secretory pathway. They are of ancient evolutionary origin supporting respiration, DNA replication, transcription, translation, the biosynthesis of steroids, heme, catabolism of purines, hydroxylation of xenobiotics, and cellular sulfur metabolism...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29447225/low-apolipoprotein-a-i-levels-in-friedreich-s-ataxia-and-in-frataxin-deficient-cells-implications-for-therapy
#15
QingQing Wang, Lili Guo, Cassandra J Strawser, Lauren A Hauser, Wei-Ting Hwang, Nathaniel W Snyder, David R Lynch, Clementina Mesaros, Ian A Blair
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure...
2018: PloS One
https://www.readbyqxmd.com/read/29406711/iscu-m108i-and-iscu-d39v-differ-from-wild-type-iscu-in-their-failure-to-form-cysteine-desulfurase-complexes-containing-both-frataxin-and-ferredoxin
#16
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (SDA), exhibits a requirement for frataxin (FXN), assembly on variant ISCU(M108I) has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that ISCU(M108I) populates only the structured state as does another variant ISCU(D39V). We have compared the properties ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and in the overall Fe-S cluster assembly reaction...
February 6, 2018: Biochemistry
https://www.readbyqxmd.com/read/29341839/activation-of-frataxin-protein-expression-by-antisense-oligonucleotides-targeting-the-mutant-expanded-repeat
#17
Liande Li, Xiulong Shen, Zhongtian Liu, Michaela Norrbom, Thazha P Prakash, Daniel O'Reilly, Vivek K Sharma, Masad J Damha, Jonathan K Watts, Frank Rigo, David R Corey
Friedreich's Ataxia (FA) is an inherited neurologic disorder caused by an expanded GAA repeat within intron 1 of the frataxin (FXN) gene that reduces expression of FXN protein. Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA...
January 17, 2018: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29329987/quantitative-proteomics-in-friedreich-s-ataxia-b-lymphocytes-a-valuable-approach-to-decipher-the-biochemical-events-responsible-for-pathogenesis
#18
Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre
Friedreich's ataxia (FRDA) represents the most frequent type of autosomal-recessively inherited ataxia and is caused by the deficiency of frataxin, a mitochondrial protein. It is known that frataxin-deficiency leads to alterations in cellular and mitochondrial iron metabolism and impacts in the cell physiology at several levels. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. Currently, cellular antioxidant defense is dysregulated when frataxin is deficient, which exacerbates oxidative damage in FRDA...
April 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29325611/autosomal-recessive-cerebellar-ataxias
#19
Brent L Fogel
The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29325032/effect-of-diazoxide-on-friedreich-ataxia-models
#20
Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio
Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway...
March 15, 2018: Human Molecular Genetics
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