Reversible axonal dystrophy by calcium modulation in frataxin-deficient sensory neurons of YG8R mice

Belén Mollá, Diana C. Muñoz-Lasso, Fatima Riveiro1, Arantxa Bolinches-Amorós, Federico V. Pallardó, Angel Fernandez-Vilata, Maria D. Vaya, Francesc Palau and Pilar Gonzalez-Cabo; Front. Mol. Neurosci. doi:10.3389/fnmol.2017.00264

We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.

Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia

Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhD Michele Yang, MD Peter Bauer, MD Arnulf H. Koeppen, MD; Journal of Neuropathology & Experimental Neurology, Volume 76, Issue 8, 1 August 2017, Pages 665–675, doi:10.1093/jnen/nlx047

The pathologic phenotype in homozygous and compound heterozygous FA is determined by residual frataxin levels rather than unique mutations.

Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich's ataxia

Shannon Chiang, Danuta S. Kalinowski, Patric J. Jansson, Des R. Richardson, Michael L.-H. Huang, Friedreich's ataxia, Neurochemistry International, Available online 4 August 2017, ISSN 0197-0186, doi:10.1016/j.neuint.2017.08.002.

Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism.

Chondrial Announces FDA Orphan Drug Designation for CTI-1601, a Novel Investigational Technology for the Treatment of Friedreich's Ataxia

BALA CYNWYD, Pa., Aug. 3, 2017 /PRNewswire/ -- Chondrial Therapeutics, Inc., an emerging biotechnology company focused on the treatment of rare mitochondrial diseases, announced today that the US Food and Drug Administration (FDA) has granted orphan drug designation to its lead investigational drug candidate, CTI-1601, being developed for the treatment of Friedreich's Ataxia.

The importance of international collaboration for rare diseases research: a European perspective

D Julkowska, C P Austin, C M Cutillo, D Gancberg, C Hager, J Halftermeyer, A H Jonker, L P L Lau, I Norstedt, A Rath, R Schuster, E Simelyte and S van Weely; Gene Therapy advance online publication 27 July 2017; doi: 10.1038/gt.2017.29

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

Impact of diabetes in the Friedreich ataxia clinical outcome measures study

Ashley McCormick, Jennifer Farmer, Susan Perlman, Martin Delatycki, George Wilmot, Katherine Matthews, Grace Yoon, Chad Hoyle, Sub H. Subramony, Theresa Zesiewicz, David R. Lynch and Shana E. McCormack; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.439

DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.

Pharmacological therapeutics in Friedreich Ataxia: The present state

Cassandra Strawser, Kimberly Schadt, Lauren Hauser, Ashley McCormick, Mckenzie Wells, Jane Larkindale, Hong Lin & David R Lynch; Expert Review of Neurotherapeutics Vol. 0 , Iss. ja,0, Accepted author version posted online: 20 Jul 2017 doi: 10.1080/14737175.2017.1356721

Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Angelical S. Martin, Dennis M. Abraham, Kathleen A. Hershberger, Dhaval P. Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J. Muehlbauer, Paul A. Grimsrud, Jason W. Locasale, R. Mark Payne, and Matthew D. Hirschey, JCI Insight. 2017;2(14):e93885. doi: 10.1172/jci.insight.93885.

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. Our data define a clear role for SIRT3 in mediating the beneficial effects of NMN in this HF model; thus, future studies in the FXN-KO and dKO models would be of interest to evaluate the consequences of manipulating of redox-induced acetylation versus SIRT3-regulated acetylation. These studies include studies dedicated to varying the NMN dosing regimen, as well as acetyl-proteomic analysis of hearts from these NMN-treated mice. Our findings presented here serve as important preclinical data to highlight NMN supplementation and/or SIRT3 agonist treatment as potential therapeutic strategies in FRDA patients and HF.

Interrogating the “unsequenceable” genomic trinucleotide repeat disorders by long-read sequencing

Qian Liu, Peng Zhang, Depeng Wang, Weihong Gu and Kai Wang; Genome Medicine 20179:65 DOI: 10.1186/s13073-017-0456-7

Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably.

In this study, we have developed RepeatHMM to detect repeat counts of microsatellites from long-read sequencing data. RepeatHMM was evaluated on both simulation data and real data and our results suggested that RepeatHMM was effective and efficient to quantify repeat counts. RepeatHMM is flexible to handle repeat patterns of any length beyond trinucleotide repeats and can incorporate different error profiles. With the wider application of long-read sequencing techniques in research and clinical settings, RepeatHMM is expected to contribute to the quantification of repeat counts and to facilitate the analysis of genotype-phenotype relationships for disease-related microsatellites.

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients

M. Seco-Cervera, D. González-Rodríguez, J. S. Ibáñez-Cabellos, L. Peiró-Chova, P. González-Cabo, E. García-López, J. J. Vílchez, I. Sanz-Gallego, F. V. Pallardó & J. L. García-Giménez; Scientific Reports 7, Article number: 5237 (2017) doi:10.1038/s41598-017-04996-9

miR-323a-3p as a biomarker for diagnosis of cardiomyopathy in FRDA

Circulating miRNAs can detect pathological events, and could also monitor molecular signals participating in cardiomyopathy even before the appearance of clinical cardiac manifestations. To maximize the likelihood of detecting the onset or progression of cardiomyopathy, we suggest combining standard cardiac diagnostic procedures with the use of circulating microRNAs. This approach could provide more clinical information for evaluating cardiomyopathy progression in FRDA. In summary, miRNAs obtained in this study show new candidates for personalized therapy in FRDA patients.