Identification of p38 MAPK as a novel therapeutic target for Friedreich\u2019s ataxia

M Grazia Cotticelli,Avinash Kaur,Yongping Wang,Shujuan Xia,Eric Ruff,John W Tobias,Robert B Wilson,Daniel Lin

doi:10.1038/s41598-018-23168-x

Abstract

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA.

Highlights

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder characterized by progressive ataxia, areflexia, dysarthria, sensory loss, and hypertrophic cardiomyopathy. (Recent reviews include those by Koeppen and Mazurkiewicz[1], Collins[2], and Gomes and Santos)[3]
To rule out that gFA11 conferred a non-specific growth advantage unrelated to the FRDA phenotype, we tested whether stable expression of gFA11 increased growth in U937 cells, in MCF-10 cells, and in apparently healthy primary human fibroblasts
The Senescence Associated Secretion Phenotype develops under conditions of genotoxic stress, in which cumulative DNA damage induces cell-cycle arrest and, through p38 activation, triggers the secretion of cytokines, IL-6 and IL-8

Summary

Introduction

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder characterized by progressive ataxia, areflexia, dysarthria, sensory loss, and hypertrophic cardiomyopathy. (Recent reviews include those by Koeppen and Mazurkiewicz[1], Collins[2], and Gomes and Santos)[3]. The gene-expression profiles of patient cells were consistent with the presence of genotoxic stress, which correlated with ages of disease onset, frataxin mRNA expression levels, and scores on the International Cooperative Ataxia Rating Scale (ICARS). Based on these data, it was suggested that FRDA cells might decrease their growth rate as a homeostatic response to chronic genotoxic stress, thereby maximizing lifespan. We show that p38 phosphorylation is increased in patient-derived cells and that inhibition of p38 reverses the growth defect of primary FRDA fibroblasts These results highlight the possible use of p38 inhibitors as therapeutic agents for FRDA

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Conclusion