Molecular approaches for the treatment and prevention of Friedreich's ataxia

Yang, Wei; Thompson, Bruce; Kwa, Faith A.A.

doi:10.1016/j.drudis.2021.11.003

Cited by 5 publications

(4 citation statements)

References 67 publications

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“…The most recent strategies are now targeting the lack of FXN, which is the primary defect of FRDA, as this is expected to have the highest therapeutic benefit ( Yang et al, 2021 ). Three different approaches are currently under development: increase of frataxin expression, delivery of recombinant frataxin protein and restoration of the frataxin locus by gene therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Several therapeutic strategies targeting either the primary or secondary defects of FRDA are under development following two main directions: (1) restoration of FXN levels using gene expression modulators, protein stabilizers and gene therapy and (2) alleviation of secondary cellular defects such as mitochondrial functions, iron accumulation, oxidative stress and ferroptosis ( Clay et al, 2019 ; Zesiewicz et al, 2020 ; Lynch and Farmer, 2021 ; Ocana-Santero et al, 2021 ; Pallardó et al, 2021 ; Yang et al, 2021 ). Hereby, pharmacologic approaches including iron-chelators, antioxidants, NRF2 activators, ferroptosis inhibitors and molecules improving mitochondrial functions have reached clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

et al. 2022

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Friedreich’s ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70–98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

et al. 2022

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“…The pathogenic mechanism of Friedreich’s ataxia at the gene level is relatively clear. The GAA trinucleotide repeat sequence amplified in the first intron of the frataxin gene is the most common mutation in the frataxin gene, inducing a substantial reduction in the concentration of the mitochondrial protein frataxin [ 131 ]. Conceptually, FRDA is a disorder of iron distribution rather than simply an overload.…”

Section: Other Iron-related Neurological Diseasesmentioning

confidence: 99%

Iron Metabolism in Aging and Age-Related Diseases

Tian

Yuan

et al. 2022

IJMS

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Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases.

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“…Regarding the IL-10 gene, three CpG islands near to the promoter around the −1087 polymorphism were methylated in peripheral blood cells and gingival tissues. B cells treatment with 5-aza-deoxycytidine (5-aza), the inhibitor of DNA methylation, increased IL-10 mRNA whatever the genotype of the −1087 SNP [69].…”

Section: Dna Methylation In Periodontal Diseasementioning

confidence: 99%

Epigenetics and Stem Cells Applications in Periodontal Therapy

Kafa

2024

Dentistry

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While periodontitis is closely linked with pathogen outgrowth, many patients have the risk of recurrence after therapy. Variations of inflammatory genes are associated with an increased susceptibility of periodontitis. Epigenetics can regulate these gene expression. In this chapter, we will highlight on the potential role of epigenetic changes in different facets, more particularly in genes involved in inflammation. Epigenetics act through remodeling of chromatin and can selectively activate or inactivate genes, determining their expression. Epigenetics could play an essential role in understanding the mechanism of gene-environment interactions, and the factors which stimulate periodontitis and reduce its response to therapy are now the subject of many studies. Also, mesenchymal stem cells (MSCs) are a promising source to regenerate periodontal tissues. They could be a good alternative to the adopted therapies, ignoring the artificial biomaterial limitations. They could be considered as a natural process for periodontium regeneration and has an immunomodulatory role to resolute the infection. For this reason, it is necessary to investigate and evaluate MSCs applicability in humans, and their clinical approach involved in regeneration of periodontal tissues.

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Molecular approaches for the treatment and prevention of Friedreich's ataxia

Cited by 5 publications

References 67 publications

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Iron Metabolism in Aging and Age-Related Diseases

Epigenetics and Stem Cells Applications in Periodontal Therapy

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