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.