Hajar Mikaeili, Madhavi Sandi, Aurélien Bayot, Sahar Al-Mahdawi & Mark A. Pook; Scientific Reports, volume 8, Article number: 17217 (2018). doi:10.1038/s41598-018-35639-2
Our results show that knocking down FAST-1 in FRDA fibroblast cells increases FXN gene expression (Fig. 10). Therefore, it can be concluded that, since FAST-1 is associated with epigenetic repression of the FXN gene, inhibition of FAST-1 may be an approach to increase the FXN transcripts and stimulate subsequent protein expression. Indeed, our results demonstrate that knocking down FAST-1 in FRDA results in a significant increase in aconitase enzyme activity, a good indicator of frataxin function within cells. Our data suggest that since FAST-1 is associated with FXN gene silencing, inhibition of FAST-1 may be an approach for FRDA therapy. Considering the nature of NATs and the fact that many currently available drugs would not affect the activity of non-coding RNA molecules, developing new methods to disrupt the function of NATs seems necessary.
Thursday, November 22, 2018
Wednesday, November 21, 2018
NMR as a Tool to Investigate the Processes of Mitochondrial and Cytosolic Iron-Sulfur Cluster Biosynthesis
Cai, K.; Markley, J.L.; Molecules 2018, 23, 2213. doi:10.3390/molecules23092213
Defects in protein components of the mitochondrial ISC machinery are associated with numerous diseases, including Friedreich ataxia (defects in frataxin), myopathy (defects in ISCU or FDX2), and multiple mitochondrial dysfunction syndromes (defects in NFU1, BOLA3, ISCA2, and IBA57). Extensive investigations over the past two decades have identified many new components and established key steps in the ISC machinery. A growing number of diseases associated with ISC defects are being discovered through clinical, genetic, and biochemical studies.
Defects in protein components of the mitochondrial ISC machinery are associated with numerous diseases, including Friedreich ataxia (defects in frataxin), myopathy (defects in ISCU or FDX2), and multiple mitochondrial dysfunction syndromes (defects in NFU1, BOLA3, ISCA2, and IBA57). Extensive investigations over the past two decades have identified many new components and established key steps in the ISC machinery. A growing number of diseases associated with ISC defects are being discovered through clinical, genetic, and biochemical studies.
Tuesday, November 20, 2018
Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes
Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Clementina Mesaros, David R. Lynch & Ian A. Blair; Scientific Reports volume 8, Article number:17043 (2018) DOI:10.1038/s41598-018-35346-y
The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.
The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.
Sunday, November 18, 2018
Emerging and Dynamic Biomedical Uses of Ferritin
Brian Chiou and James R. Connor; Pharmaceuticals 2018, 11(4), 124; doi:10.3390/ph11040124
Review
One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.
Review
One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.
Friday, November 16, 2018
Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties
Caridad Pontes, Juan Manuel Fontanet, Roser Vives, Aranzazu Sancho, Mònica Gómez-Valent, José Ríos, Rosa Morros, Jorge Martinalbo, Martin Posch, Armin Koch, Kit Roes, Katrien Oude Rengerink, Josep Torrent-Farnell and Ferran Torres; Orphanet Journal of Rare Diseases 2018 13:206 doi:10.1186/s13023-018-0926-z
The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.
The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.
Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia
Zeitlberger Anna M., Thomas-Black Gilbert, Garcia-Moreno Hector, Foiani Martha, Heslegrave Amanda J., Zetterberg Henrik, Giunti Paola; Frontiers in Cellular Neuroscience 2018, 12 366, DOI=10.3389/fncel.2018.00366
This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.
This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.
Thursday, November 15, 2018
Neuromuscular diseases with hypertrophic cardiomyopathy
Cesar S.; Global Cardiology Science and Practice 2018:27 doi:10.21542/gcsp.2018.27
Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.
Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.
Wednesday, November 14, 2018
Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA
Phillip Ward, Ian H Harding, Thomas G Close, Louise A Corben, Martin B Delatycki, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F. Egan. bioRxiv 464537; doi: 10.1101/464537 (This article is a preprint and has not been peer-reviewed)
Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia
Lynch, D. R., Farmer, J. , Hauser, L. , Blair, I. A., Wang, Q. Q., Mesaros, C. , Snyder, N. , Boesch, S. , Chin, M. , Delatycki, M. B., Giunti, P. , Goldsberry, A. , Hoyle, C. , McBride, M. G., Nachbauer, W. , O'Grady, M. , Perlman, S. , Subramony, S. H., Wilmot, G. R., Zesiewicz, T. and Meyer, C. (2018), Ann Clin Transl Neurol. . doi:10.1002/acn3.660
Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
Wednesday, October 31, 2018
Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons
Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093
We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.
We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.
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