Friday, July 6, 2018

Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering

Kai Cai, Ronnie O. Frederick, Hesam Dashti, John L. Markley; Structure, 2018, doi:10.1016/j.str.2018.05.017.

We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance.

Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration

Mohammad Hosein Farzaei, Devesh Tewari, Saeideh Momtaz, Sandro Argüelles, Seyed Mohammad Nabavi, Food and Chemical Toxicology, 2018, doi:10.1016/j.fct.2018.07.010.

Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.

Thursday, July 5, 2018

The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population

Kim JS, Kwon S, Ki CS, Youn J, Cho JW.; J Clin Neurol. 2018 Jul;14(3):374-380. Doi:10.3988/jcn.2018.14.3.374

Although the AR ataxias such as ataxia telangiectasia or FRDA are prevalent in most countries, they are extremely rare in the Korean population.26 In addition, genetic screening did not detect FRDA in the patients with undetermined ataxia. Therefore, routine screening of the FTX gene in the Korean population might not be needed unless patients show a clinical phenotype of FRDA.
FRDA is extremely rare, and to the best of our knowledge has never detected in the Korean population. In addition, phenotypes of patients in whom FRDA screening test was performed, did not correspond with FRDA.

Monday, July 2, 2018

Frataxin Restoration in the Nervous System: Possibilities for Gene Therapy

David R. Lynch, Elizabeth Kichula, and Hong Lin. Molecular Therapy, Available online 30 June 2018, ISSN 1525-0016, doi:10.1016/j.ymthe.2018.06.006

Many obstacles beyond those identified in the present study will appear in the translation of gene therapy from animal concept to human therapy. Still, the present work provides proof that gene therapy may be useful long term in FRDA, and hope for all those with this disorder.

Friday, June 29, 2018

Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study

Imis Dogan, Sandro Romanzetti, Claire Didszun, Shahram Mirzazade, Dagmar Timmann, Carsten Saft, Ludger Schöls, Matthis Synofzik, Ilaria A Giordano, Thomas Klockgether, Jörg B Schulz, Kathrin Reetz; Journal of Neurology, Neurosurgery & Psychiatry, June 2018 DOI:10.1136/jnnp-2018-318422

Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA.

Wednesday, June 27, 2018

Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil

Helena Fussiger, Maria Luiza Saraiva-Pereira, Sandra Leistner-Segal, Laura Bannach Jardim. Cerebellum (2018). doi:10.1007/s12311-018-0958-x

Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.

Autonomic function testing in Friedreich’s ataxia

Elisabetta Indelicato, Alessandra Fanciulli, Jean-Pierre Ndayisaba, Wolfgang Nachbauer, Andreas Eigentler, Roberta Granata, Julia Wanschitz, Werner Poewe, Gregor K. Wenning, Sylvia Boesch. J Neurol (2018). Doi:10.1007/s00415-018-8946-0

FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.

Tuesday, June 26, 2018

Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells

VANCOUVER, British Columbia, June 25, 2018 (GLOBE NEWSWIRE) -- Novoheart (“Novoheart” or the “Company”) (TSX-V:NVH) (FWB:3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.

FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.

“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.

Monday, June 25, 2018

Mitohormesis, an Antiaging Paradigm

Clea Bárcena, Pablo Mayoral, Pedro M. Quirós, International Review of Cell and Molecular Biology, Academic Press, ISSN 1937-6448, doi:10.1016/bs.ircmb.2018.05.002.

Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.

Sunday, June 24, 2018

Frataxin‐Mediated PINK1‐Parkin‐Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin

Liu, P. , Lin, H. , Xu, Y. , Zhou, F. , Wang, J. , Liu, J. , Zhu, X. , Guo, X. , Tang, Y. and Yao, P. (2018), Mol. Nutr. Food Res.. Accepted Author Manuscript. . doi:10.1002/mnfr.201800164

Naturally occurring quercetin has been found to induce mitophagy and prevent non‐alcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not.