Wednesday, August 24, 2016

Movement disorders in mitochondrial diseases

Tranchant, Anheim. Rev Neurol (Paris). 2016 Jul 28. pii: S0035-3787(16)30025-X. doi: 10.1016/j.neurol.2016.07.003.

Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns–Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function.

Tuesday, August 23, 2016

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Nishaki Mehta, Paul Chacko, James Jin, Tam Tran, Thomas W. Prior, Xin He, Gunjan Agarwal, and Subha V. Raman (2016). Texas Heart Institute Journal: August 2016, Vol. 43, No. 4, pp. 305-310.

We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.

Monday, August 22, 2016

Tech giants moving into health may widen inequalities and harm research, unless people can access and share their data, warn John T. Wilbanks and Eric J. Topol.

John T. Wilbanks & Eric J. Topol, Nature 535, 345–348 (21 July 2016) doi:10.1038/535345a

Nature-Comment OPEN

Citizens worldwide have too long a history of being passive players in health care — blindly following instructions from providers. And studies that have tracked reactions to revelations about global surveillance programmes suggest that most people are resigned to the idea that ownership and control of personal information is incompatible with the Internet age.

Yet just as social networking has rocketed around the world in a decade, a worldwide knowledge resource could soon be used to identify the best course of treatment for an individual on the basis of the experiences of millions. This resource will never be built unless each of us takes responsibility for our own health and disease, and for the information that we can generate about ourselves. When it comes to control over our own data, health data must be where we draw the line.

Drug screening: Drug repositioning needs a rethink

Xianting Ding, Nature 535, 355 (21 July 2016) doi:10.1038/535355d  Published online 20 July 2016

Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones. Disease is often an integration of multiple pathologies, so these are potentially treatable with different drug combinations that act in synergy.

For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.

Sunday, August 21, 2016

Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: the IMAGE-FRDA study.

Selvadurai LP , Harding IH , Corben LA , Stagnitti MR , Storey E , Egan GF , Delatycki MB , Georgiou-Karistianis N
J Neurol [2016] doi:10.1007/s00415-016-8252-7

This study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.

Saturday, August 20, 2016

Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo

Rowena Schultz; Otto W. Witte; Christian Schmeer; Investigative Ophthalmology & Visual Science August 2016, Vol.57, 4115-4124. doi:10.1167/iovs.16-19260
OPEEN ACCES This work is licensed under a Creative Commons 

Friday, August 19, 2016

Lentivirus-meditated frataxin gene delivery reverses genome instability in Friedreich ataxia patient and mouse model fibroblasts

Khonsari H , Schneider M , Al-Mahdawi S , Chianea YG , Themis M , Parris C , Pook MA , Themis M; Gene Therapy accepted article preview 12 August 2016; doi: 10.1038/gt.2016.61


Wednesday, August 17, 2016

Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich's Ataxia

Emanuela Piermarini, Daniele Cartelli, Anna Pastore, Giulia Tozzi, Claudia Compagnucci, Ezio Giorda, Jessica D’Amico, Stefania Petrini, Enrico Bertini E, Graziella Cappelletti and Fiorella Piemonte, Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw260, First published online: August 11, 2016

We hypothesize that oxidative stress, determined by high GSSG levels, induces axonal retraction by interfering with MT dynamics. We propose a mechanism of the axonopathy in FRDA where GSSG overload and MT de-polymerization are strictly interconnected. Indeed, using a frataxin-silenced neuronal model we show a significant reduction of neurites extension, a shift of tubulin toward the unpolymerized fraction and a consistent increase of glutathione bound to the cytoskeleton.

Sunday, August 14, 2016

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Oleksandr Gakh, Wasantha Ranatunga, Douglas Y. Smith IV, Eva-Christina Ahlgren, Salam Al-Karadaghi, James R. Thompson and Grazia Isaya. JBC, First Published on August 12, 2016 doi: 10.1074/jbc.M116.738542

Thursday, August 11, 2016

Characterization of Novel Small-Molecule NRF2 Activators: Structural and Biochemical Validation of Stereospecific KEAP1 Binding

Carlos Huerta, Xin Jiang, Isaac Trevino, Christopher F. Bender, Deborah A. Ferguson, Brandon Probst, Kerren K. Swinger, Vincent S. Stoll, Philip J. Thomas, Irina Dulubova, Melean Visnick, W. Christian Wigley, Biochimica et Biophysica Acta (BBA) - General Subjects, Available online 27 July 2016, ISSN 0304-4165, doi:10.1016/j.bbagen.2016.07.026.

Clinical trials of omaveloxolone are currently underway in several indications, including Friedreich’s Ataxia, mitochondrial myopathies, corneal endothelial cell loss following cataract surgery, and melanoma. The increased risk for acute fluid overload adverse events observed in BEACON with late-stage CKD patients has not been observed in subsequent studies with bardoxolone methyl or omaveloxolone.