Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093

We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease.

Kasai Shuya, Mimura Junsei, Ozaki Taku, Itoh Ken. Frontiers in Veterinary Science 5,242 2018 DOI=10.3389/fvets.2018.00242

In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.

Patients in research: still many roadblocks

Roos Eric C. BMJ 2018; 363 :k4387 doi:10.1136/bmj.k4387

Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.

Full partnership with patients is essential to any modern research enterprise

Wicks Paul, Richards Tessa, Denegri Simon, Godlee Fiona. Patients’ roles and rights in research BMJ 2018; 362 :k3193  doi:10.1136/bmj.k3193

Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.

Patients’ roles and rights in research- Patients in research: one step in a long path

Wicks P, Richards T, Denegri S, Godlee F. BMJ 2018;362:k3193. 10.1136/bmj.k3193 30045909

We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.

Unraveling the Role of Heme in Neurodegeneration

Chiabrando Deborah, Fiorito Veronica, Petrillo Sara, Tolosano Emanuela. Frontiers in Neuroscience 12 (2018) 712 DOI=10.3389/fnins.2018.00712

Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.

The impact of histone post-translational modifications in neurodegenerative diseases

Samantha N. Cobos, Seth A. Bennett, Mariana P. Torrente, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.10.019.

Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Schirinzi, T., Romano, A., Favetta, M., Sancesario, A., Burattini, R., Summa, S., Della Bella, G., Castelli, E., Bertini, E., Petrarca, M., … Vasco, G. (2018). Frontiers in neurology, 9, 849. doi:10.3389/fneur.2018.00849

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.

A case series of hereditary cerebellar ataxias in a highly consanguineous population from Northeast Brazil

Deborah Moreira Rangel, Paulo Ribeiro Nóbrega, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim, Pedro Braga-Neto, Parkinsonism & Related Disorders, 2018, ISSN 1353-8020, doi:10.1016/j.parkreldis.2018.10.027.

A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.

Intraepidermal Nerve Fiber Density in Friedreich’s Ataxia

Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Dagmar Rudzki, Julia Wanschitz, Sylvia Boesch; Journal of Neuropathology & Experimental Neurology, , nly100, doi:10.1093/jnen/nly100

In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.

Investigating the landscape of US orphan product approvals

Kathleen L. Miller and Michael Lanthier, Orphanet Journal of Rare Diseases 2018 13:183, doi:10.1186/s13023-018-0930-3

The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations.

The deoxyribose phosphate lyase of DNA polymerase β suppresses a processive DNA synthesis to prevent trinucleotide repeat instability

Yanhao Lai, Yossi Weizmann, Yuan Liu. Nucleic Acids Research, Volume 46, Issue 17, 28 September 2018, Pages 8940–8952, Doi:10.1093/nar/gky700

The results indicate that pol β dRP lyase activity restrained the pol β-dRP interaction to suppress a pol β processive DNA synthesis, thereby preventing TNR deletion. This further implicates a potential of pol β dRP lyase inhibition as a novel treatment of TNR-expansion diseases.

Ion Mobility-Mass Spectrometry Reveals Details of Formation and Structure for GAA·TCC DNA and RNA Triplexes

Jiawei Li, Alexander Begbie, Belinda J. Boehm, Alexander Button, Charles Whidborne, Yannii Pouferis, David M. Huang, Tara L. Pukala. J. Am. Soc. Mass Spectrom. (2018). https://doi.org/10.1007/s13361-018-2077-9

DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia. We demonstrate that, contrary to other examples, parallel triplex structures are favored for these sequences and that stability is enhanced by increasing oligonucleotide length and decreasing pH. We also provide evidence for the self-association of these triplexes, consistent with a proposed model of higher order DNA structures formed in Friedreich’s ataxia. By comparing triplex assembly using DNA- and RNA-based triplex-forming oligonucleotides, we demonstrate more favorable formation of RNA triplexes, suggesting a role for their formation in vivo.

New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases

Nuñez, M.T.; Chana-Cuevas, P. Pharmaceuticals 2018, 11, 109. doi:10.3390/ph11040109


Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.

Ferrochelatase activity of plant frataxin

Alejandro M. Armas, Manuel Balparda, Agustina Terenzi, Maria V. Busi, Maria A. Pagani, Diego F. Gomez-Casati, Biochimie, 2018 doi:10.1016/j.biochi.2018.10.009

These results suggest that frataxin could be the iron donor in the final step of heme synthesis in plant mitochondria, and constitutes an important advance in the elucidation of the mechanisms of heme synthesis in plants.

Calcium Deregulation: Novel Insights to Understand Friedreich’s Ataxia Pathophysiology

Abeti R, Brown AF, Maiolino M, Patel S and Giunti P (2018) . Front. Cell. Neurosci. 12:264. doi: 10.3389/fncel.2018.00264

Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for the cellular wellbeing but more importantly to generate action potential in both neurons and cardiomyocytes. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. This phenomenon is due to the excess of oxidative stress under FRDA like conditions and the consequent aberrant modulation of key players at the SR/ER and mitochondrial level that usually restore the Ca2+ homeostasis. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy.

Developmental and Neurodegenerative Damage in Friedreich Ataxia

Rezende TJR, Martinez ARM, Faber I, Girotto K, Martins MP, de Lima FD, Lopes-Cendes I, Cendes F, França MC; Eur J Neurol. Accepted Author Manuscript. . doi:10.1111/ene.13843

Structural damage in FRDA begins in spinal cord, inferior cerebellar peduncle as well as red nucleus, and progresses to cerebral areas in adulthood. These results shed some light in the early FRDA stages and highlight potential neuroimaging markers for therapeutic trials.

Corneal Confocal Microscopy: Neurologic Disease Biomarker in Friedreich's Ataxia

Odelya E. Pagovich MD Mary L. Vo MD Zijun Zhao BA Ioannis N. Petropoulos PhD Michelle Yuan BA Buntitar Lertsuwanroj MD Jessica Ciralsky MD Edward Lai MD Szilard Kiss MD Donald J. D'Amico MD Jason G. Mezey PhD Rayaz A. Malik PhD Ronald G. Crystal MD; Ann Neurol. Accepted Author Manuscript. First published: 07 October 2018, doi:10.1002/ana.25355

CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameters generated equations that predict the neurologic severity of FRDA.

Mitochondrial Targeting in Neurodegeneration: A Heme Perspective

Veronica Fiorito, Deborah Chiabrando and Emanuela Tolosano; Pharmaceuticals 2018, 11(3), 87; doi:10.3390/ph11030087

Mitochondrial dysfunction has achieved an increasing interest in the field of neurodegeneration as a pathological hallmark for different disorders. The impact of mitochondria is related to a variety of mechanisms and several of them can co-exist in the same disease. The central role of mitochondria in neurodegenerative disorders has stimulated studies intended to implement therapeutic protocols based on the targeting of the distinct mitochondrial processes. The review summarizes the most relevant mechanisms by which mitochondria contribute to neurodegeneration, encompassing therapeutic approaches. Moreover, a new perspective is proposed based on the heme impact on neurodegeneration. The heme metabolism plays a central role in mitochondrial functions, and several evidences indicate that alterations of the heme metabolism are associated with neurodegenerative disorders. By reporting the body of knowledge on this topic, the review intends to stimulate future studies on the role of heme metabolism in neurodegeneration, envisioning innovative strategies in the struggle against neurodegenerative diseases.

Automated functional upper limb evaluation of patients with Friedreich ataxia using serious games rehabilitation exercises

Bruno Bonnechère, Bart Jansen, Inès Haack, Lubos Omelina, Véronique Feipel, Serge Van Sint Jan and Massimo Pandolfo; Journal of NeuroEngineering and Rehabilitation 201815:87 doi.org/10.1186/s12984-018-0430-7

The use of new technologies in rehabilitation, including SG, is becoming increasingly important. In this study demonstrated that it is possible to combine rehabilitation exercises using SG and automated upper limb functional assessment in FRDA patients in wheelchairs. Future works are needed to determine if such kind of solution can be successfully integrated in the rehabilitation program and whether the kind of data presented in this paper can be used to predict disease progression.

Electrophysiological study of patients with spinocerebellar and Friedreich's ataxia

Blerim Myftiu, Mehmet Barış Baslo, Elif Kocasoy Orhan; Neurol Sci Neurophysiol 2018; 35: 138-144 DOI: 10.5152/NSN.2018.11239

Polyneuropathy is frequently detected in SCA and FRDA patients. The sensory nerves in lower extremities were predominantly involved; however motor dysfunction was also noted. MUNE can offer quantitative information on motor nerve fiber and motor neuron involvement. Nerve conduction studies and needle EMG demonstrate clinical or subclinical polyneuropathy in patients with SCA and FRDA ataxia. MUNE might present another parameter for peripheral involvement.

Effects of a wearable proprioceptive stabilizer on kinematics and spatio-temporal gait parameters in young with genetic ataxias

A. Romano, M. Favetta, T. Schirinzi, G. Vasco, S. Summa, S. Minosse, E. Castelli, M. Petrarca; Gait & Posture , Volume 66 , S33 Doi:10.1016/j.gaitpost.2018.07.152

Genetic ataxias are a degenerative disease of cerebellum, brain stem, and spinal cord, in which gait and limb ataxia are key clinical features. Focal mechanical vibration was found effective in improve limb and gait ataxia in adults with hereditary ataxias. Equistasi® is a medical wearable device composed by nanotechnology fibers that transform body temperature into mechanical able to generate a variation of muscle length of max 0.002 mm. This is a preliminary study to evaluate the effect of Equistasi® focal mechanical vibration on kinematic and spatio-temporal parameters in three young patients with genetic ataxias through 3D gait analysis.

The importance of central auditory evaluation in Friedreich's ataxia

Zeigelboim BS, Teive HAG, Rosa MRD, Malisky JS, Fonseca VR, Marques JM, Liberalesso PB. Arq Neuropsiquiatr. 2018 Mar;76(3):170-176. doi: 10.1590/0004-282x20180008.

Objective To assess central auditory function in Friedreich's ataxia. Methods A cross-sectional, retrospective study was carried out. Thirty patients underwent the anamnesis, otorhinolaryngology examination, pure tone audiometry, acoustic immittance measures and brainstem auditory evoked potential (BAEP) assessments. Results The observed alterations were: 43.3% in the pure tone audiometry, bilateral in 36.7%; 56.6% in the BAEP test, bilateral in 50%; and 46.6% in the acoustic immittance test. There was a significant difference (p < 0.05) in the comparison between the tests performed. Conclusion In the audiological screening, there was a prevalence of the descending audiometric configuration at the frequency of 4kHz, and absence of the acoustic reflex at the same frequency. In the BAEP test, there was a prevalence of an increase of the latencies in waves I, III and V, and in the intervals of interpeaks I-III, I-V and III-V. In 13.3% of the patients, wave V was absent, and all waves were absent in 3.3% of patients.