Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Noemí Esteras, Albena T. Dinkova-Kostova, Andrey Y. Abramov. Biological Chemistry. Volume 397, Issue 5, Pages 383–400, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2015-0295, January 2016

As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies.

Cardiac Serum Biomarkers in Friedreich Ataxia May Reflect Fibrosis, Myocyte Injury, and Degree of Hypertrophy

C. Bui, R.B. Wilson, D.R. Lynch, J.W. Rossano, O. Elci, K.Y. Lin, The Journal of Heart and Lung Transplantation, Volume 35, Issue 4, Supplement, April 2016, Page S172, ISSN 1053-2498, doi:10.1016/j.healun.2016.01.479.

We hypothesized that serum markers of cardiac injury, stress, fibrosis, and inflammation are higher in FA subjects than non-FA controls, and these markers correlate with echocardiographic markers of cardiomyopathy.

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients with Friedreich Ataxia

Pamela C. Kruger, Karl X. Yang, Patrick J. Parsons, Alyssa B. Becker, Paul J. Feustel, Arnulf H. Koeppen. The American Journal of Cardiology, Available online 20 April 2016, ISSN 0002-9149, doi: 10.1016/j.amjcard.2016.04.024.

Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA.

Idebenone in Friedreich ataxia and Leber’s hereditary optic neuropathy: close mechanisms, similar therapy?

Manuel Schiff, Pierre Rustin. Brain (2016) aww085 DOI: 10.1093/brain/aww085 First published online: 19 April 2016

"Yet despite these studies, there is no clear consensus on the benefits of idebenone therapy for patients with Friedreich ataxia. Nevertheless, being essentially harmless idebenone has been, and is still, given to many patients with Friedreich ataxia all over the world."

However, for legal and/or marketing reasons, recent idebenone authorization for LHON resulted in some patients with Friedreich ataxia having difficulty obtaining it.

So far the occurrence of potential responders to idebenone in Friedreich ataxia has not been rigorously examined, but in view of the data obtained in LHON, defining a subgroup of therapy-responder patients appears a reasonable objective for next trials in this (and other) rare disease.

Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Subrahamanyam Dantham, Achal K. Srivastava, Sheffali Gulati, Moganty R. Rajeswari, Journal of the Neurological Sciences, Available online 14 April 2016, ISSN 0022-510X, doi:10.1016/j.jns.2016.04.016.

Despite several therapies under study or in development for FRDA, evaluation of therapeutic efficacy is limited by the lack of minimally invasive biomarkers to assess disease progression and severity.
Our study identified three major findings, 1. FRDA patients showed decrease in the levels of plasma mtDNA, whereas plasma nDNA was increased. 2. Plasma mtDNA has shown to exhibit high sensitivity and specificity in discriminating FRDA patients from the healthy controls over plasma nDNA levels 3. Significant serial changes have been observed in case of plasma mtDNA upon intervention with nutrient supplement (omega-3 fatty acids).
In view of their neuro-cardio protective role and positive effect on mitochondrial metabolism in ameliorating the neuro symptoms, the Omega-3 fatty acids (Eicosapentaenoic acid and docosahexaenoic acid) have been recommended as a nutritional supplement

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ataxia

Belén Mollá, Fátima Riveiro, Arantxa Bolinches-Amorós, Diana C. Muñoz-Lasso, Francesc Palau, Pilar González-Cabo. Disease Models and Mechanisms 2016 : doi: 10.1242/dmm.024273

OPEN ACCESS

These results confirm that the lack of frataxin induces different pathogenic mechanisms in nervous system and pancreas in the mouse model of FRDA: sensory nerve dying-back and pancreatic senescence.

Original Research Proposal: Creation of an Iron Sensing FXN mRNA Therapeutic Riboswitch for the Treatment of Friedreich's Ataxia

Stephanie Mack, Das Research Group, Department of Chemistry, Carnegie Mellon University

 Location: Mellon Institute Room 355

Development of an AAV9 coding for a 3XFLAG-TALEfrat#8-VP64 able to increase in vivo the human frataxin in YG8R mice

P Chapdelaine, C Gérard, N Sanchez, K Cherif, J Rousseau, D L Ouellet, D Jauvin and J P Tremblay. Gene Ther. accepted article preview 2016 Apr 15. doi: 10.1038/gt.2016.36.

OPEN

The study indicates that an AAV coding for a TALE protein coupled with a TAD may be used to increase gene expression in vivo as a possible treatment not only for FRDA but also for other haploinsufficiency diseases.

Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia

Hayashi G, Cortopassi G. PLoS ONE 11(4): e0153574. doi:10.1371/journal.pone.0153574

OPEN ACCESS

This work demonstrates that the mRNA abundance of the oxidative stress response genes NCF2 and PDLIM1 are potential biomarkers for FA. Additionally, because NCF2 and PDLIM1 respond dose-dependently to frataxin level, they supplement and confirm the antioxidant effects of therapies that raise frataxin, increasing the number of Friedreich's relevant biomarkers to three in the lymphoblast context: frataxin, NCF2, and PDLIM1. Lastly, because PDLIM1/CLP36 has recently been shown to be responsive to Nrf2 status/oxidative stress in cardiomyocytes, it could become a valuable marker of drug effect in cardiomyocytes.

Comorbid Medical Conditions in Friedreich Ataxia: Association With Inflammatory Bowel Disease and Growth Hormone Deficiency

Julianna E. Shinnick, Kimberly Schadt, Cassandra Strawser, Nicholas Wilcox, Susan L. Perlman, George R. Wilmot, Christopher M. Gomez, Katherine D. Mathews, Grace Yoon, Theresa Zesiewicz, Chad Hoyle, S. H. Subramony, Eppie M. Yiu, Martin B. Delatycki, Alicia F. Brocht, Jennifer M. Farmer, and David R. Lynch; J Child Neurol 0883073816643408, first published on April 12, 2016 as doi:10.1177/0883073816643408

Diagnoses with more than twice the prevalence in this Friedreich ataxia cohort than the general population were growth hormone deficiency, ulcerative colitis, Crohn’s disease, and inflammatory bowel disease. However, patients with Friedreich ataxia did not have a higher incidence of other neurological disorders such as epilepsy or migraine; other sleep disorders besides sleep apnea; other cardiovascular disorders such as coronary artery disease, hypercholesterolemia, or hypertension; or psychiatric disorders such as anxiety