Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia.

Genki Hayashi,Theresa L. Pedersen,Yan Shen,John W. Newman,Mark Pook,Gino Cortopassi

doi:10.1093/hmg/ddu407

Abstract

An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.

Highlights

Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia affecting 1:40 000 individuals [1]
The cerebellar frataxin deficiency of the mouse frataxin knockin-knockout (KIKO) mouse was quantified by qRT – PCR; the animals contained 31% of frataxin compared with wild type (WT) mice as control (P . 0.0032, n 1⁄4 4)
Twelve oxylipins were elevated in the KIKO mice (P . 0.05, n 1⁄4 4) (Fig. 2), including the COX-derived prostanoids, thromboxanes, COX-side products 11 and 15 hydroxyeicosatetraenoic acids (HETE) [30], the cytochrome P450 (CYP)-derived epoxyeicosatrienoic acid (EET) and dihydroxyeicosatrienoic acid (DHET), and the 5LOX-derived HETE and ketoeicosatetraenoic acids [17,31,32]

Summary

Introduction

Friedreich’s ataxia (FRDA) is the most common autosomal recessive ataxia affecting 1:40 000 individuals [1]. Clinical symptoms of FRDA include gait ataxia affecting the motor coordination, weakness and atrophy of the extremities, and loss of lower-limb tendon reflexes. Extensive knowledge on the role of oxidative stress in the pathogenesis of FRDA exists including studies involving FRDA patient-derived cells and various mouse models. Reduced Frataxin appears to reduce the level and or inducibility of Nuclear factor (erythroid-derived 2)-like 2 (NRF2) in cell and animal models of Friedreich’s [13,14], which has been demonstrated to have anti-inflammatory effects in other systems patients may impair the induction of early antioxidant defenses resulting in increased cell lethality when under oxidative stress.

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Results

Conclusion