A case-control spectral analysis of sleep in Friedreich's Ataxia

R. Forbes, S.S. Smith, A. Ritchie, J.D. O'Sullivan, S. Mantovani, Sleep Medicine, Volume 40, Supplement 1, December 2017, Page e209, ISSN 1389-9457, doi:10.1016/j.sleep.2017.11.611.

This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.

Emerging therapeutics for the treatment of Friedreich’s ataxia

Elisabetta Indelicato & Sylvia Bösch; Expert Opinion on Orphan Drugs Vol. 6 , Iss. 1,2018 doi:10.1080/21678707.2018.1409109

Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.

Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases

Gerwyn Morris, Michael Berk, André F. Carvalho, Michael Maes, Adam J. Walker, Basant K. Puri, Behavioural Brain Research, Available online 28 December 2017, ISSN 0166-4328, doi:10.1016/j.bbr.2017.12.036.

Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter-1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q10, iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N-acetylcysteine.

Association between iron related gene polymorphisms and Friedreich’s ataxia (FRDA) disease and peripheral neuropathy in Indian cohort

I. Singh, S. Shakya, R.K. Singh, A. Istaq, V. Goyal, S. Garima, A.K. Srivastava; Journal of the Neurological Sciences Volume 381, Supplement, 15 October 2017, Pages 895 Doi: 10.1016/j.jns.2017.08.2519

Till date, this is the largest study investigating HFE variations in FRDA. The observed over representation of p.H63D variation in FRDA and its correlation with the occurrence of peripheral neuropathy is intriguing in the context of dysregulated iron metabolism in FRDA due to loss of function mutations in FXN.

Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory.

Scott W. Burnside, Giles E. Hardingham; Biochemical Society Transactions Nov 17, 2017, 45 (6) 1295-1303; DOI: 10.1042/BST20170013

Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Jun Yoshino, Joseph A. Baur, Shin-ichiro Imai,  Cell Metabolism, Available online 14 December 2017, ISSN 1550-4131, doi:10.1016/j.cmet.2017.11.002.

Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.

Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements

Tanguy Melac A, Mariotti C, Filipovic Pierucci A on behalf of the EFACTS group, et al; J Neurol Neurosurg Psychiatry Published Online First: 26 December 2017. doi: 10.1136/jnnp-2017-316964

Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.

The International Rare Diseases Research Consortium: Policies and Guidelines to maximize impact

Hanns Lochmüller, Josep Torrent i Farnell, Yann Le Cam, Anneliene H Jonker, Lilian PL Lau, Gareth Baynam, Petra Kaufmann, Hugh JS Dawkins, Paul Lasko, Christopher P Austin, Kym M Boycott & on behalf of the IRDiRC Consortium Assembly; European Journal of Human Genetics 25, 1293–1302 (2017) doi:10.1038/s41431-017-0008-z

The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research.

Exploring patient and family involvement in the lifecycle of an orphan drug: a scoping review

Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani and Tania Stafinski; Orphanet Journal of Rare Diseases 201712:188 doi:10.1186/s13023-017-0738-6

Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagnoses and limited access to effective therapies due to the high level of uncertainty in market approval and reimbursement decisions. It has been suggested that patient involvement may help to reduce some of these uncertainties. This review explored existing and proposed roles for patients, families, and patient organizations at each stage of the lifecycle of therapies for rare diseases (i.e., orphan drug lifecycle).

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia

Hong Lin, Jordi Magrane, Elisia M. Clark, Sarah M. Halawani, Nathan Warren, Amy Rattelle, David R. Lynch; Disease Models & Mechanisms 2017 10: 1529-1538; doi: 10.1242/dmm.030049

Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model.

Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich’s Ataxia

Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Agostinho G. Rocha, Andrew Dancis, Clementina A Mesaros, David R. Lynch, and Ian Alexander Blair; Anal. Chem., Just Accepted Manuscript DOI: 10.1021/acs.analchem.7b04590 Publication Date (Web): December 22, 2017

Frataxin is undetectable in serum or plasma, and whole blood cannot be used because it is present in long-lived erythrocytes. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of 10-days. The assay is based on stable isotope dilution immunopurification two-dimensional nano-ultrahigh performance liquid chromatography/parallel reaction monitoring/mass spectrometry. The lower limit of quantification was 0.078 pg frataxin/μg protein and the assay had 100% sensitivity and specificity for discriminating between controls and FA cases. The mean levels of control and FA platelet frataxin were 9.4 2.6 pg/g protein and 2.4 0.6 pg/g protein, respectively. The assay should make it possible to rigorously monitor the effects of therapeutic interventions on frataxin expression in this devastating disease.

Somatic instability of the expanded GAA repeats in Friedreich’s ataxia

Ashlee Long, Jill S. Napierala, Urszula Polak, Lauren Hauser, Arnulf H. Koeppen, David R. Lynch, Marek Napierala; PLoS ONE 12(12): e0189990. Doi:10.1371/journal.pone.0189990

Friedreich’s ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7–9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient’s lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation.

Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal

Muñoz Lasso, DC. (2017). Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal [Tesis doctoral no publicada]. Universitat Politècnica de València. doi:10.4995/Thesis/10251/92842

Friedreich ataxia (FRDA) is a recessive human disease of central and peripheral nervous system that affects children and young adults. FRDA is a peripheral neuropathy characterized by a initial degeneration of the large neurons of the dorsal root ganglia (DRG) or proprioceptive neurons. Most of the patients with FRDA have a homozygous guanine-adenine-adenine (GAA) expansion within the first intron of the gen that codifies for a small mitochondrial protein, frataxin (FXN). This mutation leads to a reduction of frataxin expression in all human cells, which produces changes in both the cell and mitochondrial physiology, resulting in a dysfunction of the mitochondrial energetic metabolism linked to the increase of oxidative stress and calcium dyshomeostasis. These cellular proceses are tightly related with the regulation of the actin and microtubule cytoskeletons and with vesicle trafficking. Here, we show how the absence of frataxin in the mouse models YG8R and YG8sR affects the axonal cytoskeleton of adult sensory neurons. Changes of actin and microtubule cytoskeletons and the failure of Ca 2+ signaling induce alterations of dynamics growth cones of sensory neurons, which in turn produce a reduction of their capacity to grow and regenerate their axons. This study shows how these events can lead to the neurodegeneration in Friedreich's ataxia.

Development of an iron-selective antioxidant probe with protective effects on neuronal function

García-Beltrán O, Mena NP, Aguirre P, Barriga-González G, Galdámez A, Nagles E, et al. (2017). PLoS ONE 12(12): e0189043. doi:10.1371/journal.pone.0189043

ron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer’s diseases, Friedreich ataxia and Huntington’s disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

Health-related quality of life among adults with diverse rare disorders

Kathleen R. Bogart and Veronica L. Irvin; Orphanet Journal of Rare Diseases 201712:177 doi:10.1186/s13023-017-0730-1

Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-related quality of life (HRQL) research has been restricted to single RDs, small samples, or non-validated measures. This study reports HRQL among adults with diverse RDs, and compares their scores to those of the U.S. population and people with common chronic health conditions.

Biochemical Analyses of Human Iron–Sulfur Protein Biogenesis and of Related Diseases

Oliver Stehling, Viktoria D. Paul, Janina Bergmann, Somsuvro Basu, Roland Lill, Methods in Enzymology, Academic Press, ISSN 0076-6879, doi:10.1016/bs.mie.2017.11.004.

Maturation of Fe/S proteins in mammals is an intricate process mediated by two assembly systems located in the mitochondrial and cytosolic–nuclear compartments. Malfunction particularly of the mitochondrial system gives rise to severe neurological, metabolic, or hematological disorders, often with fatal outcome. In this chapter, we describe approaches for the differential biochemical investigation of cellular Fe/S protein maturation in mitochondria, cytosol, and nucleus. The analyses may also facilitate the identification of the affected Fe/S protein assembly step in diseased state. As Fe/S cluster insertion into target apoproteins is a frequent determinant of protein stability, examination of protein steady-state levels in biological samples frequently permits reliable first clues about the maturation process. In some specific cases, this approach allows the assessment of enzymatic or regulatory functions of Fe/S proteins, including the formation of lipoate cofactor by mitochondrial lipoic acid synthase or the posttranscriptional regulation of transferrin receptor and ferritin expression by the cytosolic iron regulatory proteins. More direct Fe/S protein maturation assays like enzymatic analyses may further validate the observed maturation defects. Here, we present a simple protocol for the determination of dihydropyrimidine dehydrogenase enzyme activity by thin-layer chromatography. In order to directly monitor Fe/S cluster insertion into target apoproteins, we have developed a 55Fe radiolabeling technique tracing the in vivo Fe/S cofactor formation in mammalian tissue culture. The combination of the presented techniques represents a comprehensive strategy to assess the multiple facets of Fe/S protein assembly for both mechanistic analyses and for the elucidation of specific defects in Fe/S diseases.

Computational drug repositioning for rare diseases in the era of precision medicine

Brian Delavan, Ruth Roberts, Ruili Huang, Wenjun Bao, Weida Tong, Zhichao Liu, Drug Discovery Today, 2017, , ISSN 1359-6446, doi:10.1016/j.drudis.2017.10.009.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.

Depressive symptoms in Friedreich ataxia

Antonieta Nieto, Atteneri Hernández-Torres, Javier Pérez-Flores, Fernando Montón, International Journal of Clinical and Health Psychology, Available online 8 December 2017, ISSN 1697-2600, doi:10.1016/j.ijchp.2017.11.004.

Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. Method: The study groups consisted of 57 patients with a diagnosis of FRDA. The Beck Depression Inventory-II was used to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients’ scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. Our data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms.

Mitochondrial pore opening and loss of Ca2 + exchanger NCLX levels occur after frataxin depletion

R. Purroy, E. Britti, F. Delaspre, J. Tamarit, J. Ros, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 6 December 2017, ISSN 0925-4439, doi:10.1016/j.bbadis.2017.12.005.

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Friedreich ataxia: Clinical feature and electrophysiological symptoms

Oguri M. ; J Neurosci Rural Pract [serial online] 2017 [cited 2017 Dec 6];8:691-2. DOI: 10.4103/jnrp.jnrp_248_17

The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities. In general, results of electrophysiologic studies including visual, auditory brainstem, and somatosensory-evoked potentials are often abnormal.

Iron-induced oligomerization of human FXN 81-210 and bacterial CyaY frataxin and the effect of iron chelators

Eva-Christina Ahlgren, Mostafa Fekry, Mathias Wiemann, Christopher A. Söderberg, Katja Bernfur, Olex Gakh, Morten Rasmussen, Peter Højrup, Cecilia Emanuelsson, Grazia Isaya, Salam Al-Karadaghi. PLoS ONE 12(12): e0188937. doi:10.1371/journal.pone.0188937

Patients suffering from the progressive neurodegenerative disease Friedreich’s ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form.

C-Path And FARA Announce Collaborative Data Aggregation Project For Friedreich’s Ataxia

Tucson, AZ, and Downingtown, PA — Dec. 4, 2017 — Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) have announced that they will work together to develop an aggregated database of clinical data for Friedreich's ataxia (FA). Use of this database will promote collaborative research to support the understanding of natural history, potential biomarkers, and potential clinical endpoints for patients with FA, which will help researchers develop more efficient clinical trial protocols to test new therapies more quickly and effectively.

The project will establish an integrated database of clinical data for FA that can be shared and utilized by existing FA researchers. It will enlist companies that have carried out clinical trials in FA to obtain contributions of clinical data, as well as sharing natural history data collected by FARA's collaborative clinical research network.

The role of oxidative stress in Friedreich's ataxia

Federica Lupoli, Tommaso Vannocci, Giovanni Longo, Neri Niccolai and Annalisa Pastore. FEBS Letters, DOI: 10.1002/1873-3468.12928

Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia.

Peripheral nerve ultrasound in Friedreich ataxia

Mulroy, E., Pelosi, L., Leadbetter, R., Joshi, P., Rodrigues, M., Mossman, S., Kilfoyle, D. and Roxburgh, R. (2017). Muscle Nerve. doi: 10.1002/mus.26012

The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.
Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role.

Synthetic transcription elongation factors license transcription across repressive chromatin

Graham S. Erwin, Matthew P. Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N. Syed, Asuka Eguchi, Md. Ashraf, Justin Jeffery, Mousheng Xu, Paul M. C. Park, Hasan Mukhtar, Achal K. Srivastava, Mohammed Faruq, James E. Bradner, Aseem Z. Ansari; Science 30 Nov 2017 eaan6414, Published Online 30 Nov 2017 DOI: 10.1126/science.aan6414

The molecule being tested is designed to assist the enzyme that reads, or “transcribes,” DNA at the confusing repeats. Once it reaches the other side, the enzyme, called RNA polymerase, reads the gene and makes RNA that in turn codes for frataxin, the protein that is lacking in Friedreich’s ataxia.

Designer molecule points to treatment for diseases caused by DNA repeats

University of Wisconsin–Madison news, November 30, 2017 By David Tenenbaum.


Using a molecule designed to overcome a roadblock formed by a common type of genetic flaw, researchers at the University of Wisconsin–Madison have made progress towards novel molecular treatments for Friedreich’s ataxia — a rare but fatal disorder — in the laboratory dish and in animals.