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Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich's Ataxia

ANTIOXIDANTS (2020)

Journal

ANTIOXIDANTS

Volume 9, Issue 12, Pages -

Publisher

MDPI

DOI: 10.3390/antiox9121257

Keywords

Friedreich’ s ataxia; oxidative stress; thioredoxins; glutaredoxins

Funding

FIS from the ISCIII [FIS:PI19/010846]
CIBERer-ISCIII [ACCI-2018-22, ACCI-2019-22]
Federacion Espanola de Ataxias de Espana (FEDAES) grant
Generalitat Valenciana Grant [PROMETEO/2018/135]
Spanish Ministry of Science and Innovation
Instituto de Salud Carlos III through CIBERer (Biomedical Network Research Center for Rare Diseases)
Instituto de Salud Carlos III through (INGENIO2010)
European Regional Development Funds (ERDF) at the University of Valencia
European Regional Development Funds (ERDF)

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Abstract

The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich's ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

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Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Marta Medina-Carbonero, Arabela Sanz-Alcazar, Elena Britti, Fabien Delaspre, Elisa Cabiscol, Joaquim Ros, Jordi Tamarit

Summary: Friedreich Ataxia is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin gene. The most common mutation is a GAA expansion in the first intron of the gene, resulting in decreased frataxin expression. By introducing a specific mutation into the murine Fxn gene, researchers have analyzed the consequences of this mutation in vivo. They found that mice with this mutation displayed low frataxin levels in all tissues, neurological deficits resembling those in FA patients, and mitochondrial alterations. The researchers concluded that the primary pathological mechanism underlying this mutation is frataxin deficiency, suggesting frataxin replacement therapies may benefit patients with this mutation.

CELLULAR AND MOLECULAR LIFE SCIENCES (2022)