A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

Ryan J. McGinty, Franco Puleo, Anna Y. Aksenova, Julia A. Hisey, Alexander A. Shishkin, Erika L. Pearson, Eric T. Wang, David E. Housman, Claire Moore, Sergei M. Mirkin, Cell Reports, Volume 20, Issue 10, 5 September 2017, Pages 2490-2500, ISSN 2211-1247, doi:10.1016/j.celrep.2017.08.051

Engineered Axonal Tracts as “Living Electrodes” for Synaptic-Based Modulation of Neural Circuitry

M. D. Serruya, J. P. Harris, D. O. Adewole, L. A. Struzyna, J. C. Burrell, A. D. Nemes, D. Petrov, R. H. Kraft, H. I. Chen, J. A. Wolf, D. K. Cullen, Adv. Funct. Mater. 2017, doi:10.1002/adfm.201701183

Brain–computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel “biohybrid” strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologically-based vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based “living electrodes”, which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain.

Friedrich’s ataxia: Patients develop severe motor impairments in the absence of pro­prioceptive and epicritic signals from the periphery. Living electrodes could provide an articial sensory arc: by tapping into signals from periphery (such as strain gauges, accelero­meters and gyroscopes worn at joints in all four limbs, or from implanted cuff recordings of peripheral nerves), living electrodes implanted into primary sensory cortices could pro­vide sensory feedback and allow improved voluntary move­ ment and functional independence. Grown with glutamatergic neurons, these living electrodes could be implanted to termi­nate in layer IV of the post­central gyrus; because living elec­trodes are themselves quite small, multiple constructs could be implanted corresponding to different joints (e.g., gyros from the left knee driving a living electrode implanted in the right medial sensory cortex, left elbow and shoulder to right lateral sensory cortex, and viceversa for the right extremities and left hemisphere).

Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.

Tracey A. Rouault and Nunziata Maio; The Journal of Biological Chemistry 292, 12744-12753. doi: 10.1074/jbc.R117.789537

Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins.

Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia

Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao & Kuanyu Li; Scientific Reports 7, Article number: 9840 (2017) doi:10.1038/s41598-017-10320-2

We demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia.
In summary, SS-31 treatment improves the morphology and function of mitochondria in the FRDA patient-derived cells by upregulating the expression of FXN at the translational level and reducing oxidative stress. In addition, SS-31 treatment significantly enhances the ability of patient-derived cells to withstand challenges from exogenous oxidative stress. The mechanism of the translational upregulation in FXN expression by mitochondrion-targeted SS-31 needs to be further addressed. However, improvement in the quality of mitochondria in FRDA patient–derived cells by SS-31 treatment appears promising. It is reasonable to suggest that SS-31 might potentially be a new drug for the early treatment of FRDA.

Overexpression of Drosophila frataxin triggers cell death in an iron-dependent manner

Oliver Edenharter, Janik Clement, Stephan Schneuwly & Juan A. Navarro, Journal of Neurogenetics Vol. 0 , Iss. 0,0; doi:10.1080/01677063.2017.1363200

In this work, we have increased frataxin expression in neurons to elucidate specific roles that frataxin might play in these tissues. Using molecular, biochemical, histological and behavioral methods, we report that frataxin overexpression is sufficient to increase oxidative phosphorylation, modify mitochondrial morphology, alter iron homeostasis and trigger oxidative stress-dependent cell death. Interestingly, genetic manipulation of mitochondrial iron metabolism by silencing mitoferrin successfully improves cell survival under oxidative-attack conditions, although enhancing antioxidant defenses or mitochondrial fusion failed to ameliorate frataxin overexpression phenotypes. This result suggests that cell degeneration is directly related to enhanced incorporation of iron into the mitochondria. Drosophila frataxin overexpression might also provide an alternative approach to identify processes that are important in FRDA such as changes in mitochondrial morphology and oxidative stress induced cell death.

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Jeffrey R. Liddell, Antioxidants 2017, 6(3), 65; doi:10.3390/antiox6030065

This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.

Jupiter Orphan Therapeutics Receives Orphan Drug Designation for its Trans-Resveratrol Product JOTROL for Treatment of Friedreich's Ataxia

JUPITER, Fla., Aug. 22, 2017 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT"), Jupiter, FL, today announced that it has received notification from the US Food and Drug Administration (FDA) that its Orphan Drug Designation request for trans-Resveratrol has been granted.

"Orphan Drug Designation serves as an important milestone for JOT as it positions our JOTROL™ product as a potential treatment for FA. We are hopeful that JOTROL™ can ultimately provide a meaningful treatment for FA patients around the world based on the earlier Phase II trial, utilizing resveratrol, conducted by our partner Murdoch Children's Research Institute, Melbourne, Australia ("MCRI"). That trial was an open label trial and generated very encouraging results, where 4 out of 5 very important endpoints were met. We, JOT together with MCRI, expect to repeat these results through a larger placebo controlled study utilizing JOTROL™ to avoid the Gastro Intestinal (GI) tolerability issues.

Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells

Daniela Giustarini, Graziano Colombo, Maria Lisa Garavaglia, Emanuela Astori, Nicola Marcello Portinaro, Francesco Reggiani, Salvatore Badalamenti, Anna Maria Aloisi, Annalisa Santucci, Ranieri Rossi, Aldo Milzani, Isabella Dalle-Donne, Free Radical Biology and Medicine, Available online 12 August 2017, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2017.08.008.

Glutathione (GSH) is the major non-protein thiol in humans and other mammals, which is present in millimolar concentrations within cells, but at much lower concentrations in the blood plasma. GSH and GSH-related enzymes act both to prevent oxidative damage and to detoxify electrophiles. Under oxidative stress, two GSH molecules become linked by a disulphide bridge to form glutathione disulphide (GSSG). Therefore, assessment of the GSH/GSSG ratio may provide an estimation of cellular redox metabolism. Current evidence resulting from studies in human blood, solid tissues, and cultured cells suggests that GSH also plays a prominent role in protein redox regulation via S-glutathionylation.

By immunohistochemistry with anti-GSH antibody, PSSG were also detected in Friedreich's ataxia, an autosomal recessive disorder caused by mutations in the gene encoding frataxin. In particular, in the cervical sections of spinal cord derived from autopsies of individuals with Friedreich's ataxia, immunostaining with anti-GSH antibodies was significantly stronger than in control sections, suggesting a significant increase in PSSG amount in all grey matter neurons, particularly in motor neurons of the anterior horns, as well as in the axonal spinal tracts (mostly in posterior white columns, spinocerebellar and corticospinal tracts). These findings suggest the occurrence of oxidative stress in the spinal cord of patients with Friedreich's ataxia as a consequence of reduced frataxin expression.

European Reference networks for rare diseases: what is the conceptual framework?

Véronique Héon-Klin, Orphanet Journal of Rare Diseases 201712:137 doi:10.1186/s13023-017-0676-3

In February 2017, 24 European Reference Networks (ERNs) were established in a European legal framework, of which 23 are dedicated to rare or low prevalence complex diseases or conditions. More than 300 hospitals and 900 highly specialised teams are participating in the approved ERN.

The ERNs are an opportunity to explore these changes and turn them into assets for patients with unmet needs. If we succeed in promote knowledge exchange in such a way that patients will only be treated in duly justified cases in the “other” MS, then “the European social model in health” can be preserved under the current European treaties.

Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease

Yabe I, Sasaki H.; Brain Nerve. 2017 Aug;69(8):913-924. doi: 10.11477/mf.1416200842.
[Article in Japanese]
We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.