Frataxin: from the sequence to the biological role

Pignataro MF, Noguera ME, Herrera MG, Roman EA, Santos J. Frataxin: from the sequence to the biological role. Biophys Rev. 2025 Apr 3;17(2):449-465. doi: 10.1007/s12551-025-01311-z. PMID: 40376404; PMCID: PMC12075029. 

In this review, we focused on different aspects concerning the biophysics and the biochemistry of frataxin and its partners, as well as on the current knowledge regarding proteostasis and post-translational modifications. The involvement of frataxin and its partners in diseases will also be addressed, including the current therapeutic approaches. Finally, a section is dedicated to understanding the phylogenetic distribution of frataxin.

Cerebellar grey matter volume predicts cerebellar tDCS efficacy in individuals with Friedreich ataxia

Gilles Naeije, Christian Georgiev, Pierre Cabaraux, Mathieu Bourguignon; Cerebellar grey matter volume predicts cerebellar tDCS efficacy in individuals with Friedreich ataxia, Clinical Neurophysiology, 2025, 2110744, ISSN 1388-2457, doi:10.1016/j.clinph.2025.2110744. 

FA patients exhibited significantly reduced cerebellar gray matter volume compared to controls (p = 0.024) after intracranial volume correction, skin-to-cerebellum distance did not differ between groups (p = 0.11). Stepwise linear regression analysis disclosed that the anterior cerebellar gray matter volume was a significant predictor of SARA improvement (β = −0.18, p < 0.001) and the posterior cerebellar gray matter volume of CCAS-S improvement (β = −0.13, p 0.023). Neither SCP diameter nor skin-to-cerebellum distance significantly impacted ctDCS efficacy. Cerebellar gray matter volume is associated to ctDCS-induced symptoms improvements in FA.

Predictive machine learning and multimodal data to develop highly sensitive, composite biomarkers of disease progression in Friedreich ataxia

Saha, S., Corben, L.A., Selvadurai, L.P. et al. Predictive machine learning and multimodal data to develop highly sensitive, composite biomarkers of disease progression in Friedreich ataxia. Sci Rep 15, 17629 (2025). doi:10.1038/s41598-025-01047-6 

 This study pioneers the development of clinically relevant, multidomain, fully objective composite biomarkers of disease severity and progression, using multimodal neuroimaging and background data (i.e., demographic, disease history, genetics). Data from 31 individuals with FRDA and 31 controls from a longitudinal multimodal natural history study IMAGE-FRDA, were included.

Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich’s Ataxia-GAA Repeats

Park, Joohyun, Claudia Dufke, Zofia Fleszar, Michael Schlotterbek, Elena Buena-Atienza, Lara G. Stühn, Caspar Gross, Marc Sturm, Stephan Ossowski, Ludger Schöls, and et al. 2025. "Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich’s Ataxia-GAA Repeats" International Journal of Molecular Sciences 26, no. 11: 4969. doi:10.3390/ijms26114969 

 Genetic testing included fragment analysis, gene panel analysis and exome sequencing, which only detected one pathogenic heterozygous missense variant (c.389 G>T,p.Gly130Val) in FXN. Although conventional repeat analyses failed to detect GAA expansions in our patient, subsequent short-read genome sequencing (GS) indicated a potential GAA repeat expansion. This finding was confirmed by long-read GS, which in addition revealed a complex pattern of interruptions. Both large and small GAA expansions with divergent interruptions containing G, A, GA, GAG and/or GAAG sequences were present within one allele, indicating mosaic sequence variations. Our findings underscore the complexity of repeat expansions which can exhibit both interruptions and somatic instability. We also highlight the utility of long-read GS in unraveling intricate genetic profiles, ultimately contributing to more accurate diagnoses in clinical practice.

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia

Inhibition of Rho-associated kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia. Minggang Fang, Shahid Banday, Sara K. Deibler, Tessa M. Simone, Madison Coleman, Emerald O’Connor, Rui Li, Lihua Julie Zhu, Michael R. Green, Journal of Neuroscience 22 May 2025, e2307242025; DOI: 10.1523/JNEUROSCI.2307-24.2025 

 Through an RNA interference screen, we identified ROCK1 and ROCK2 kinases as critical repressors of FXN expression, making them promising therapeutic targets for upregulating FXN in patient-derived cells. Treatment with small-molecule ROCK inhibitors, including the FDA-approved drug belumosudil and clinically advanced fasudil, restores frataxin levels, alleviates mitochondrial defects, and improves disease phenotypes in cells and animal models. These findings establish ROCK kinases as targets for Friedreich ataxia therapy and open new avenues for repurposing existing ROCK inhibitors, warranting clinical exploration.