Saturday, May 17, 2025
5/17/2025
p38 MAPK activation as a therapeutic target for Friedreich ataxia - PROJECT SUMMARY/ABSTRACT There are no approved therapies for the autosomal-recessive neuro- and cardio-degenerative disorder Friedreich ataxia (FA). FA is caused by hypomorphic mutations in the gene encoding the protein frataxin. Frataxin localizes to the mitochondrial matrix and functions in the biogenesis of iron-sulfur-clusters (ISCs), which are important prosthetic groups for both intra- and extra-mitochondrial enzymes. We found that the p38 MAP kinase stress- response pathway is constitutively hyperactivated in FA cells, likely as a result of ongoing oxidative stress and/or an ongoing DNA damage response (DDR). Our working hypothesis is that chronic hyperactivation of the p38 pathway, which modulates a key protein in the ISC biogenesis complex, is part of a maladaptive feedback loop that further suppresses ISC biogenesis in FA cells; hence, inhibition of the p38 pathway, or of its activation, counteracts the deleterious effects of decreased frataxin function. Our preliminary studies have implicated lipid peroxidation and telomere damage in FA pathogenesis, both of which activate p38, and both of which are consequences of ISC deficiency. We hypothesize that ISC biogenesis in FA cells will be increased, and FA- associated defects ameliorated, by (i) inhibition of p38 and/or MK2, which links p38 to ISC biogenesis; or (ii) a reduction in p38 activation, either through a decrease in oxidative stress (particularly lipid peroxidation) or a decrease in the DDR (particularly secondary to critical telomere shortening). Complemented by genetic approaches, we will test compounds that are known to target these pathways, allowing us to elucidate the roles of these pathways in FA pathogenesis while simultaneously advancing our overall goal of identifying and prioritizing compounds for potential clinical development. Our Specific Aims are: Aim 1. To use fibroblast models to interrogate the interrelated roles of the p38-MAPK pathway, oxidative stress, and DNA damage in the pathogenesis of FA, and to test relevant drugs and drug targets for amelioration of FA-associated defects. We will test our hypothesis that constitutive hyperactivation of the p38 pathway in FA cells represents a maladaptive feedback loop, and that inhibiting this pathway counteracts the deleterious effects of decreased frataxin function, thereby ameliorating FA-associated defects. Using a combination of genetic and small-molecule approaches, we will test the effects of antioxidants, anti-DDR agents, and p38/MK2 inhibition on p38 activation, ISC biogenesis, and FA-associated defects. Aims 2 and 3. To use FA iPSC- derived cardiomyocytes and sensory neurons (Aim 2), and FA zebrafish (Aim 3), to test our hypotheses in affected cell types in vitro and in vivo. Using a combination of genetic and small-molecule approaches, we will test the effects of antioxidants, anti-DDR agents, and p38/MK2 inhibition on p38 activation, ISC biogenesis, and FA-associated defects validated in these models. We anticipate a significant positive impact: our preliminary studies already link these pathways to FA pathophysiology, and compounds targeting these pathways have been developed and, in some cases, are already in clinical trials for other disorders.
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