Ataxia de friedreich, revisión bibliográfica

Investigación, R. S. (2023, febrero 22). Ataxia de friedreich, revisión bibliográfica. Recuperado el 23 de febrero de 2023, de ▷ RSI - Revista Sanitaria de Investigación website: https://revistasanitariadeinvestigacion.com/ataxia-de-friedreich-revision-bibliografica/ 

La ataxia de Friedreich es una enfermedad hereditaria y neurodegenerativa rara que afecta a personas jóvenes que se caracteriza por un deterioro lentamente progresivo de la coordinación en la marcha y en la capacidad para mantener correctamente la postura corporal, así como otros signos y síntomas neurológicos. Es la ataxia hereditaria más común con un patrón de herencia autosómica recesiva. La enfermedad causa en quienes la padecen un deterioro progresivo del cerebelo y ganglios espinales dorsales. Esta degeneración provoca en los afectados, de manera imparable, una pérdida progresiva de muchas de las funciones necesarias para una autonomía personal: pérdida de sensibilidad, descoordinación en los movimientos, escoliosis, disfagia, disartria, inmunodeficiencia, y predisposición al cáncer y en muchos casos diabetes y problemas cardíacos graves, causantes de la muerte en la mayoría de los casos. Los afectados por esta enfermedad, en un tiempo más o menos corto, acaban perdiendo toda autonomía personal.

Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model

Börklü E. Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model. Yeast (Chichester, England). 2023 Feb. DOI: 10.1002/yea.3845. PMID: 36755518. 

The comparative inquiry of transcriptome data reveals new promising roles for metformin in FRDA treatment since deferiprone and metformin treatments produce overlapping transcriptional and phenotypic responses in YFH1Δ cells. The results revealed that both deferiprone and metformin treatment does not rescue aerobic respiration in YFH1Δ cells, but they alleviate the FRDA phenotype probably by triggering the retrograde mitochondria-to-nucleus signaling.

Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia

Smith, F. M., & Kosman, D. J. (2023). Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia. bioRxiv : the preprint server for biology, 2023.02.09.527936. doi.org/10.1101/2023.02.09.527936 

We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and increased barrier permeability, cell pathologies that may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Our findings implicate other barrier cells, e.g., the cardiac microvasculature, likely contributory also to disease pathology in FRDA.

EvolClustDB: exploring eukaryotic gene clusters with evolutionarily conserved genomic neighbourhoods, Journal of Molecular Biology

Marcet-Houben, M., Collado-Cala, I., Fuentes-Palacios, D., Gómez, A. D., Molina, M., Garisoain-Zafra, A., … Gabaldón, T. (2023). EvolClustDB: exploring eukaryotic gene clusters with evolutionarily conserved genomic neighbourhoods. Journal of Molecular Biology, (168013), 168013. doi:10.1016/j.jmb.2023.168013 

The search also revealed that there were multiple CF found in the insect dataset containing Frataxin homologs (CI_005786, CI_005711, CI_005644, CI_000213, among others) and in the fungal dataset (CF_012296 and CF_009163). This shows that the Frataxin genomic context tends to be conserved, but that the specific neighboring genes are clade-specific. The functional relationship between the Frataxin-surrounding genes and Frataxin in the different clades is unknown and deserves further investigation.

Liquid chromatography-mass spectrometry analysis of frataxin proteoforms in whole blood as biomarkers of the genetic disease friedreich’s ataxia

Rojsajjakul, T., Wu, L., Grady, C. B., Hwang, W.-T., Mesaros, C., Lynch, D. R., & Blair, I. A. (2023). Liquid chromatography-mass spectrometry analysis of frataxin proteoforms in whole blood as biomarkers of the genetic disease friedreich’s ataxia. Analytical Chemistry. doi:10.1021/acs.analchem.3c00091 

These findings auger well for using frataxin levels measured by the validated stable isotope dilution ultrahigh-performance liquid chromatography–multiple reaction monitoring/mass spectrometry assay to monitor therapeutic interventions and the natural history of FRDA. Our study also illustrates the utility of using whole blood for protein disease biomarker discovery and validation.

Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide

Hatanaka J, Hashiya K, Bando T, Sugiyama H. Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide. Bioorganic & Medicinal Chemistry. 2023 Feb;81:117208. DOI: 10.1016/j.bmc.2023.117208. PMID: 36780807. 

Here, we report the synthesis of a compound that increases the transcription of FXN in cells derived from an FRDA patient. The compound was effective in lower (one tenth) concentration than the compound that previously reported. High concentration of the compound is toxic, but toxicity was reduced with a host-guest complex.

Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9

Pouiré Yaméogo, Catherine Gérard, Nathalie Majeau & Jacques P. Tremblay. Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9. Gene Ther (2023). doi:10.1038/s41434-023-00387-0

We are therefore aiming to develop FRDA treatment based on the deletion of GAAr with CRISPR/Cas9 technology using a single AAV expressing a small Cas9 (CjCas9) and two single guide RNAs (sgRNAs) targeting the FXN gene. This AAV was intraperitoneally administrated to YG8sR (250–300 GAAr) and to YG8-800 (800 GAAr) mice. DNA and RNA were extracted from different organs a month later. PCR amplification of part of intron 1 of the FXN gene detected some GAAr deletion in some cells in heart and liver of both mouse models, but the editing rate was not sufficient to cause an increase in frataxin mRNA in the heart. However, the correlation observed between the editing rate and the distribution of AAV suggests a possible therapy based on the removal of the GAAr with a better delivery tool of the CRISPR/Cas9 system.

Pathways to healing: plants with therapeutic potential for neurodegenerative diseases

Tyler, S. E. B., & Tyler, L. D. K. (2023). Pathways to healing: plants with therapeutic potential for neurodegenerative diseases. IBRO Neuroscience Reports. doi:10.1016/j.ibneur.2023.01.006 

This study aimed to find plants with therapeutic bioactivities for a range of NDs. 1339 of the 2001 plant species were found to have a bioactivity from the literature of therapeutic relevance to NDs such as Parkinson’s disease, Huntington’s disease, AD, motor neurone diseases, multiple sclerosis, prion diseases, Neimann-Pick disease, glaucoma, Friedreich's ataxia and Batten disease. 43 types of bioactivities were found, such as reducing protein misfolding, neuroinflammation, oxidative stress and cell death, and promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, and anti-microbial activity. Ethno-led plant selection was more effective than random selection of plant species. Our findings indicate that ethnomedicinal plants provide a large resource of ND therapeutic potential.

Bioactive fumarate improves cardiac function and expands lifespan in Friedrech’s ataxia

Salinas, L., Figueroa, F., Montgomery, C. B., Thai, P. N., Chiamvimonvat, N., Dugar, S., Sen, S., Cortopassi, G., & Dedkova, E. N. (2023). Bioactive fumarate improves cardiac function and expands lifespan in Friedrech’s ataxia. Biophysical Journal, 122(3), 96a. doi:10.1016/j.bpj.2022.11.714 

 Friedreich's ataxia (FA) is a recessive ataxia caused by reduction of mitochondrial protein, frataxin (FXN). Cardiomyopathy is the leading cause of death in FA patients due to deficient FXN expression in the heart. We have developed a novel monomethyl fumarate prodrug, IMF, which has improved pharmacokinetic profile and compared its effect to fumarate prodrug dimethyl fumarate (DMF, Tecfidera).

Genome-Wide Identification, Characterization and Expression Profiling of Potato (Solanum tuberosum) Frataxin (FH)

Kurt F, Filiz E, Yildiz K, Akbudak MA. Genome-Wide Identification, Characterization and Expression Profiling of Potato (Solanum tuberosum) Frataxin (FH) Gene. Genes. 2023; 14(2):468. https://doi.org/10.3390/genes14020468 

The FH genes were found to have a lineage-specific distribution and were more conserved in monocots than in dicots. While multiple copies of FH genes have been reported in some species, including plants, only one isoform of FH was found in potato. The expression of StFH in leaves and roots was analyzed under two different abiotic stress conditions, and the results showed that StFH was upregulated more in leaves and that its expression levels increased with the severity of the stress. This is the first study to examine the expression of an FH gene under abiotic stress conditions.