Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat

Li Liande, Shen Xiulong, Liu Zhongtian, Norrbom Michaela, Prakash Thazha P., O'Reilly Daniel, Sharma Vivek K., Damha Masad J., Watts Jonathan K., Rigo Frank, and Corey David R.. January 2018, ahead of print.doi:10.1089/nat.2017.0703

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. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.

Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich’s ataxia fibroblasts

De Samber B, Meul E, Laforce B, De Paepe B, Smet J, De Bruyne M, et al. (2018). PLoS ONE 13(1): e0190495. doi:10.1371/journal.pone.0190495

Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Jan Ježek, Katrina F. Cooper and Randy Strich; (Review) Antioxidants 2018, 7(1), 13; doi: 10.3390/antiox7010013

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Dinkova-Kostova, A. T., Kostov, R. V. and Kazantsev, A. G. (), The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14379

The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

Utilidad del tratamiento como uso compasivo de mecasermina (factor de crecimiento insulínico recombinante humano tipo 1) en ataxia de Friedreich

A. García Ron, M. Rodriguez Mesa, Neurología, Available online 12 January 2018, ISSN 0213-4853, doi:10.1016/j.nrl.2017.11.004.

Neuropathische Fußfehlstellungen

Falk Thielemann, Lea Franken, Lars Heubner, Stefan Rammelt, Jens Goronzy, Fuß & Sprunggelenk, Available online 12 January 2018, ISSN 1619-9987, doi:10.1016/j.fuspru.2017.11.007.

Abstract: Zusammenfassung
Ein wesentlicher Fokus der Therapie von Patienten mit neurologischer Erkrankung liegt auf der Förderung, dem Erhalt bzw. der Wiederherstellung von motorischen Funktionen. Muskuläre Tonusstörungen, tarsale Gelenkinstabilitäten und fixierte Fehlstellungen der Füße sind häufig Teilaspekte einer komplexen Störung der gesamten Funktionskette. Ihre Behandlung erfolgt interdisziplinär unter Berücksichtigung assoziierter Komorbiditäten und ist abhängig von der Art und dem Schwergrad der neurologischen Störung, dem Alter des Patienten und der Flexibilität der Deformität. Das Indikationsspektrum zur Stabilisierung oder Korrektur neuropathischen Fußdeformität umfasst unterschiedliche konservative und operative Verfahren.

Summary
Treatment of patients with neurological disorders focuses on the promotion, the maintenance and the restoration of motor function. Muscular dysbalance, tarsal joint instabilities and fixed foot deformities are often partial aspects of a complex dysfunction of the entire functional chain. Their treatment is multidisciplinary, taking into account associated conditions and comorbidities, and is dependent on the nature and severity of the neurological disorder, the age of the patient and the flexibility of the deformity. The treatment options for the stabilisation or correction of neuropathic foot deformities include a variety of conservative and operative procedures.
Schlüsselwörter: üsselwörterPes cavus; Pes equinovarus; Pes planovalgus; infantile Zerebralparese; Instabilität; cavus foot; club foot; flat foot; infantile cerebral palsy; instability

Emotion Recognition and Psychological Comorbidity in Friedreich’s Ataxia

Teresa Costabile, Veronica Capretti, Filomena Abate, Agnese Liguori, Francesca Paciello, Chiara Pane, Anna De Rosa, Silvio Peluso, Giuseppe De Michele, Alessandro Filla, Francesco Saccà; Cerebellum (2018). doi:10.1007/s12311-018-0918-5

Little effort has been made to understand the psychological and emotional burden of the disease. The aim of our study was to measure patients’ ability to recognize emotions using visual and non-verbal auditory hints, and to correlate this ability with psychological, neuropsychological, and neurological variables. FRDA patients have impaired emotion recognition that may be secondary to neuropsychological impairment. Depression and anxiety were not higher in FRDA as compared to HC and should not be considered as part of the disease.

Biophysical characterisation of the recombinant human frataxin precursor

Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini and Javier Santos; FEBS Open Bio (2018). Accepted Article. DOI: 10.1002/2211-5463.12376

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. His6-TAT-FXN1-210 was expressed in E. coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing.

Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

Juan A. Navarro and Stephan Schneuwly; Front Genet. 2017; 8: 223. Published online 2017 December 21. doi: 10.3389/fgene.2017.00223

Similar contradictory findings have been recently described in a Drosophila model of Friedreich's ataxia (FRDA). Impairment of transcription of the gene frataxin is the molecular cause underlying the disease. Most of the current evidences support a strong relation between frataxin and iron in several models, including the fly. Moreover, genetic and chemical manipulation of iron biology was found to have a positive impact in FRDA phenotypes. Remarkably, flies displaying reduced levels of frataxin also seemed to have altered levels of other metals such as Zn and Cu. Although the contribution of other metals was already suggested by studies in human samples, this fly work was the first one showing that therapies based on such metals might be beneficial. Indeed, Zn and Cu chelators improved frataxin deficiency without altering iron content. In this line, silencing either dZip42C.1, dZip42C.2 and dZip88E or dZnT35C, dZnT41F and dZnT63C also improved FRDA conditions via reduction of the iron content. All these results raise several interesting questions: Why are Cu and Zn accumulating in FRDA flies? Why does KD of genes with opposite function or acting in different cellular compartments trigger the same effect? Did they also modify the accumulation of Zn in FRDA flies? Is it possible that any of these transporters has also a mitochondrial function?

Quantitative proteomics in Friedreich's ataxia B-lymphocytes: A valuable approach to decipher the biochemical events responsible for pathogenesis

Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 9 January 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.01.010.


To better understand the biochemical sequelae of frataxin reduction, global protein expression analysis was performed using quantitative proteomic experiments in Friedreich's ataxia patient-derived B-lymphocytes as compared to controls. We were able to confirm a subset of changes in these cells and importantly, we observed previously unreported signatures of protein expression. Among the novel protein signatures that we have identified, the decrease in CHCHD4 might partly explain some aspects of the molecular pathogenesis of FRDA.

The identification of a core set of proteins changing in the FRDA pathogenesis is a useful tool in trying to decipher the function(s) of frataxin in order to clarify the mitochondrial metabolic disease process.