We are pleased to welcome Jill NAPIERALA from the Peter O’Donnell Jr. Brain Institute in Dallas, on September 18th invited by Hélène PUCCIO.
She will give a seminar at 11am entitled: “ Defining pathogenic mechanisms of Friedreich’s ataxia to reveal opportunities for therapeutic intervention ”
📍 The seminar will be in the Amphi 2 Bis, 2nd floor.
For PGNM Students and Postdocs, you can register for lunch HERE!
ABSTRACT
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN) that reduce its expression. Onset, severity, and progression of the disease all correlate with FXN levels. Frataxin is a mitochondrial protein that is translated as precursor (FXN-P) in the cytosol and undergoes sequential cleavage steps in the mitochondrial matrix, producing an intermediate (FXN-I) isoform and the mature isoform (FXN-M). Some FRDA patients carry point mutations that alter the expression of FXN isoforms, but nonetheless, result in reduced levels of the FXN-M protein when compared with carriers and healthy controls. The most prevalent missense mutation changes a glycine to valine at position 130 (G130V). Clinical features of FRDA G130V patients differ from those typically observed for the disease, and include preserved speech and upper limb functions and a slower disease progression. Unexpectedly, much less FXN-M protein is detectable in G130V patient samples compared to patient samples harboring other mutations. We and others have shown that FXN isoform expression is perturbed by the G130V mutation such that the FXN-I isoform is overrepresented. We hypothesize that the G130V mutation impairs FXN mitochondrial maturation processing or destabilizes the mature isoform and that the FXN-I isoform is functional and partially compensates for the substantial reduction of FXN-M, thus slowing disease progression and contributing to the distinct symptoms of FRDA G130V patients. Using novel patient-derived cellular models of FRDA G130V, we are determining mechanisms that govern steady state levels of endogenous FXN-G130V isoforms. We are also using transcriptomics and proteomics approaches to investigate whether this mutation confers a gain-of-function phenotype that could be linked to the atypical clinical presentation of FRDA G130V patients.
MAIN PUBLICATIONS
| 1. | Yameogo, P., Aguilar, S., Prakash, T.P., Rigo, F., Lynch, D.R., Napierala, J.S., Napierala, M. (2025). Antisense oligonucleotide therapy for patients with Friedreich’s ataxia carrying the c.165+5G>C splicing mutation. Mol Ther Nucleic Acids Jul1;36(3):102617. doi:10.1016/j.omtn.2025.102617. PMID: 40704029 |
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| 2. | Hirschfeld, A.S., Misiorek, J.O., Dabrowska, M., Muszynski, J., Gerhart, B.J., Zenczak, M., Rakoczy, M., Rolle, K., Switonski, P., Napierala, J.S., Handschuh, L., Napierala, M., and Badura-Stronka, M. (2025). Spinocerebellar ataxia 27B (SCA27B) – a systematic review and a case report of a Polish family. J. Appl. Genet 2025 Apr 29. doi: 10.1007/s13353-025-00967-3. PMID: 40299270 |
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| 3. | Mozafari, N., Milagres, S., Umek, T., Rocha, C.S.J., Vargiu, C.M., Freyberger, F., Saher, O., Napierala, M., Napierala, J.S., Blomberg, P., Jørgensen, P.T., Punga, T., Smith, C.I.E., Wengel, J., and Zain, R. (2025). Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression. Mol Ther Nucleic Acids 2025 Apr 17;36(2):102541. doi: 10.1016/j.omtn.2025.102541. PMID: 40487352 | ||
| 4. | * | Mukherjee, S., Pereboeva, L., Fil, D., Saikia, A., Lee, J., Li, J., Cotticelli, G.M., Soragni, E., Wilson, R.B., Napierala, M., Napierala, J.S. (2024) Design and validation of cell-based potency assays for frataxin supplementation treatments. Mol Ther Methods Clin Dev 2024 Dec 12; 32(4) doi: 10.1016/j.omtm.2024.101347. PMID: 39823061 | |
| 5. | Pellerin, D., Méreaux, J.-L., Bodula, S., Danzi, M., Dicaire, M.-J., Davoine, C.-S., Genis, D., Spurdens, G., Ashton, C., Hammond, J.M., Gerhart, B., Chelban , V., Le, P., Safisamghabadi, M., Yanick, C., Lee, H., Nageshwaran, S., Matos-Rodrigues, G., Jaunmuktane, Z., Petrecca, K., Akbarian, S., Nussenzweig, A., Usdin, K., Renaud, M., Bonnet, C. Ravenscroft, G., Saporta, M., Napierala, J.S., Houlden, H., Deveson, I., Napierala, M., Brice, A., Molina-Porcel , L., Seilhean, D., Züchner, S., Durr, A., Brais, B.
(2024) Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum. Brain 2024 Oct8:awae312. doi: |
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| 6. | Gerhart, B.J., Pellerin, D., Zuchner, S., Brais, B., Matos-Rodrigues, G., Nussenzweig, A., Usdin, K., Park, C.C., Napierala, J.S., Lynch, D.R., Napierala, M. (2024) Assessment of the clinical interactions of GAA repeat expansions in FGF14 and FXN. Neurology: Genetics 2024 Nov 20;10(6):e200210.doi: 10.1212/NXG.0000000000200210. PMID: 39574782 | ||
| 7. | Miellet, S., Maddock, M., Napierala, J.S., Napierala, M., Dottori, M. (2024) Generation of genetically modified Friedreich’s ataxia induced pluripotent stem cell lines and isogenic control lines carrying an inducible neurogenin-2 expression cassette. Stem Cell Res 2024 Jun 21;79:103477. doi: 10.1016/j.scr.2024.103477. PMID: 38936158 | ||
| 8. | Sayles, N.M., Napierala, J.S., Anrather, J., Diedhiou, N., Li, J., Napierala, M., Puccio, H., Manfredi, G. (2023) Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. Dis Model Mech 2023 Oct 1;16(10):dmm050114. doi: 10.1242/dmm.050114. Epub 2023 Oct. 9. PMID: 37691621 |
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| 9. | Fil, D., Conley, R.L., Zuberi, A.R., Lutz, C.M., Gemelli, T., Napierala, M., Napierala, J.S. (2023) Neurobehavioral deficits of mice expressing a low level of G127V mutant frataxin. Neurobiol Dis 2023 Feb:177:105996. doi: 10.1016/j.nbd.2023.105996. Epub 2023 Jan 10.
PMID: 36638893 |
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| 10. | * | Cotticelli, M.G., Xia, S., Truitt, R., Doliba, N.M., Rozo, A.V., Tobias, J.W., Lee, T., Chen, J., Napierala, J.S., Napierala, M., Yang, W., Wilson, R.B. (2022) Acute frataxin knockdown in induced pluripotent stem cell-derived cardiomyocytes activates a type I interferon response Dis Model Mech 16:dmm049497; PMID: 36107856 | |
| 11. | Wang D., Ho, E.S., Cotticelli, M.G., Xu, P., Napierala, J.S., Hauser, L.A., Napierala, M., Himes, B.E., Wilson, R.B., Lynch, D.R., Mesaros, C. (2022) Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich’s ataxia J Lipid Res Jul 15:100255;PMID: 35850241 | ||
| 12. | Li, Y., Li, J., Wang, J., Zhang, S., Giles, K., Prakash, T.P., Rigo, F., Napierala, J.S., Napierala, M. (2022) Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich’s ataxia Hum Mol Genet Jun 16:ddac134; PMID 35708503 | ||
| 13. | Schreiber, A.M., Li, Y., Chen, Y.H., Napierala, J.S., Napierala, M. (2022) Selected histone deacetylase inhibitors reverse the Frataxin transcriptional defect in a novel Friedreich’s ataxia induced pluripotent stem cell-derived neuronal reporter system Front Neurosci; PMID: 35281493 | ||
| 14. | Li, Y., Li, J., Wang, J., Lynch, D.R., Shen, X., Corey, D.R., Parekh, D., Bhat, B., Woo, C., Cherry, J.J., Napierala, J.S., Napierala, M. (2021) Targeting 3’ and 5’ untranslated regions with antisense oligonucelotides to stabilize frataxin mRNA and increase protein expression Nucleic Acids Res 49: 11560-11574;PMID: 34718736 | ||
| 15. | Napierala, J.S., Rajapakshe, K., Clark, A.D., Chen, Y-Y., Huang, S., Mesaros, C., Xu, P., Blair, I.A., Hauser, L.A., Farmer, J., Lynch, D.R., Edwards, D.P., Coarfa, C., Napierala, M.
(2021) Reverse phase protein array reveals correlation of retinoic acid metabolism with cardiomyopathy in Friedreich’s ataxia Mol Cell Proteomics; PMID: 33991687 |
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| 16. | Li, J., Li, Y., Pawlik, K., Napierala, J.S., Napierala, M. (2020) A CRISPR/Cas9, Cre/lox, and Flp/FRT cascade strategy for the precise and efficient integration of exogenous DNA into cellular genomes CRISPR J; PMID: 33146562 | ||