Chutake YK, Costello WN, Lam CC, Parikh AC, Hughes TT, Michalopulos MG, Mark A. Pook, Sanjay I. Bidichandani. (2015) FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia. PLoS ONE 10(9): e0138437. doi:10.1371/journal.pone.0138437
OPEN ACCESS
Our results indicate that FXN transcriptional deficiency in the YG8sR humanized mouse model of FRDA is caused by deficient transcriptional initiation as a result of promoter silencing. While this mechanism has previously been noted in patient-derived lymphoblastoid cell lines, our present data provide supportive evidence for the existence of this mechanism of transcriptional deficiency in fibroblasts and in multiple tissues. Our data also suggest that the mechanism underlying FXN transcriptional deficiency in FRDA is unlikely to be tissue-specific.
Our data indicate that the YG8sR humanized mouse is a reasonable model for investigating the molecular mechanism(s) underlying repeat-mediated promoter silencing in FRDA. The YG8sR mouse model would also be useful for testing drugs that are designed to reverse the transcriptional initiation defect caused by promoter silencing in FRDA, such as the 2-aminobenzamide derived histone deacetylase inhibitors.
Thursday, September 24, 2015
Tuesday, September 22, 2015
Staging of cardiomyopathy in Friedreich ataxia
Roger E. Peverill, International Journal of Cardiology, Available online 21 September 2015, ISSN 0167-5273, doi: 10.1016/j.ijcard.2015.09.047.
The combination of ECG, LGE and hsTnT with echocardiographic findings in the evaluation of these individuals is of considerable interest as it has suggested that absence of cardiac involvement in FRDA is uncommon. Whether there is any clinical significance of this finding is less certain, as it is not known whether those individuals with minor cardiac changes will ever develop cardiac symptoms or progressive cardiac disease. While the possibility of a staging system for cardiac involvement in FRDA remains of interest, the recent proposal may be considered premature given the limitations of our knowledge about the natural history of cardiac disease in FRDA.
Paper review:: The Cardiomyopathy in Friedreich’s Ataxia – New Biomarker for Staging Cardiac Involvement. Frank Weidemann, Dan Liu, Kai Hu, Cristiane Florescu, Markus Niemann, Sebastian Herrmann, Bastian Kramer, Stephan Klebe, Kathrin Doppler, Nurcan Üçeyler, Christian Oliver Ritter, Georg Ertl, Stefan Störk, International Journal of Cardiology, Available online 15 May 2015, ISSN 0167-5273, doi:10.1016/j.ijcard.2015.05.074.
The combination of ECG, LGE and hsTnT with echocardiographic findings in the evaluation of these individuals is of considerable interest as it has suggested that absence of cardiac involvement in FRDA is uncommon. Whether there is any clinical significance of this finding is less certain, as it is not known whether those individuals with minor cardiac changes will ever develop cardiac symptoms or progressive cardiac disease. While the possibility of a staging system for cardiac involvement in FRDA remains of interest, the recent proposal may be considered premature given the limitations of our knowledge about the natural history of cardiac disease in FRDA.
Paper review:: The Cardiomyopathy in Friedreich’s Ataxia – New Biomarker for Staging Cardiac Involvement. Frank Weidemann, Dan Liu, Kai Hu, Cristiane Florescu, Markus Niemann, Sebastian Herrmann, Bastian Kramer, Stephan Klebe, Kathrin Doppler, Nurcan Üçeyler, Christian Oliver Ritter, Georg Ertl, Stefan Störk, International Journal of Cardiology, Available online 15 May 2015, ISSN 0167-5273, doi:10.1016/j.ijcard.2015.05.074.
Delayed-onset Friedreich's ataxia revisited
Lecocq, C., Charles, P., Azulay, J.-P., Meissner, W., Rai, M., N'Guyen, K., Péréon, Y., Fabre, N., Robin, E., Courtois, S., Guyant-Maréchal, L., Zagnoli, F., Rudolf, G., Renaud, M., Sévin-Allouet, M., Lesne, F., Alaerts, N., Goizet, C., Calvas, P., Eusebio, A., Guissart, C., Derkinderen, P., Tison, F., Brice, A., Koenig, M., Pandolfo, M., Tranchant, C., Dürr, A. and Anheim, M. (2015). Mov. Disord.. doi: 10.1002/mds.26382
Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.”
Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.”
Monday, September 21, 2015
Does tandem walking discriminate better than normal walking among children with DCD, ataxia and healthy controls? A preliminary analysis performed with IMUs on the trunk
D. Trojaniello, A. Mannini, D. Sival, H.J. Blok, A.M. Sabatini, U. Della Croce, Gait & Posture, Volume 42, Supplement 2, September 2015, Page S10, ISSN 0966-6362,doi: 10.1016/j.gaitpost.2015.07.028.
Significant differences were found between FRDA and H children and FRDA and DCD children for most of IMU-St and IMUSp variables. Variables extracted from both IMU-Sp and IMUSt during TW were able to discriminate between FRDA and DCD children and between FRDA and H children.
Significant differences were found between FRDA and H children and FRDA and DCD children for most of IMU-St and IMUSp variables. Variables extracted from both IMU-Sp and IMUSt during TW were able to discriminate between FRDA and DCD children and between FRDA and H children.
Friday, September 18, 2015
Friedreich Ataxia: From the Eye of a Molecular Biologist
Muthuswamy, Srinivasan MSc; Agarwal, Sarita PhD; Neurologist: September 2015 - Volume 20 - Issue 3 - p 51–55 doi: 10.1097/NRL.0000000000000054
Review Article
Review Article
Thursday, September 17, 2015
Protein replacement therapy for mitochondrial disorders
M. Rapoport, D. Marcus, A. Saada, T. Erlich, R. Hadad, H. Greif, M. Lichtenstein, H. Lorberboum-Galski, Mitochondrion, Volume 24, Supplement, September 2015, Page S35, ISSN 1567-7249, doi:10.1016/j.mito.2015.07.096.
The approach is to fuse the Mitochondrial targeting Sequence (MTS), with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide]. This novel approach has been tested using different mitochondrial proteins implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAB), C6ORF66 and Frataxin, and have been evaluated in vitro, in patients' cells and in vivo, in mouse models. In patient's cells and in mice tissues, including the brain, AT-MTS-Mitochondrial fusion proteins arrive at the cells and their mitochondria rapidly and efficiently, getting an improvement of the mitochondrial functions and life span in animal models.
The approach is to fuse the Mitochondrial targeting Sequence (MTS), with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide]. This novel approach has been tested using different mitochondrial proteins implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAB), C6ORF66 and Frataxin, and have been evaluated in vitro, in patients' cells and in vivo, in mouse models. In patient's cells and in mice tissues, including the brain, AT-MTS-Mitochondrial fusion proteins arrive at the cells and their mitochondria rapidly and efficiently, getting an improvement of the mitochondrial functions and life span in animal models.
Repurposing riluzole to treat hereditary cerebellar ataxia
Heather Wood; Nature Reviews Neurology (2015) doi:10.1038/nrneurol.2015.161 Published online 15 September 2015
Given the limited availability of new therapies for neurological disease, repurposing of existing drugs is an approach that is being increasingly explored. A randomized controlled trial, conducted in Italy provides evidence that this drug could also be beneficial in patients with hereditary cerebellar ataxia, spinocerebellar ataxia and Friedreich ataxia.
Given the limited availability of new therapies for neurological disease, repurposing of existing drugs is an approach that is being increasingly explored. A randomized controlled trial, conducted in Italy provides evidence that this drug could also be beneficial in patients with hereditary cerebellar ataxia, spinocerebellar ataxia and Friedreich ataxia.
Wednesday, September 16, 2015
R loops: new modulators of genome dynamics and function
José M. Santos-Pereira & Andrés Aguilera, Nature Reviews Genetics (2015) doi:10.1038/nrg3961, Published online 15 September 2015
R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing. Importantly, Friedreich ataxia (FRDA) and fragile X syndrome (FXS) occur as a result of repeat expansions in the frataxin (FXN) and fragile X mental retardation 1 (FMR1) genes, respectively; this leads to gene silencing through H3K9me2 deposition on the expanded regions, which thus become fragile. Such expansions accumulate R loops, providing a new link among heterochromatin, R loops and replication-dependent fragility.
R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing. Importantly, Friedreich ataxia (FRDA) and fragile X syndrome (FXS) occur as a result of repeat expansions in the frataxin (FXN) and fragile X mental retardation 1 (FMR1) genes, respectively; this leads to gene silencing through H3K9me2 deposition on the expanded regions, which thus become fragile. Such expansions accumulate R loops, providing a new link among heterochromatin, R loops and replication-dependent fragility.
Monday, September 14, 2015
Jones Tendon Transfer
Richard Derner, Jeffrey Holmes, Clinics in Podiatric Medicine and Surgery, Available online 12 September 2015, ISSN 0891-8422, http://dx.doi.org/10.1016/j.cpm.2015.06.004.
Charcot-Marie-Tooth (CMT), poliomyelitis, Roussy-Le´vy syndrome, and Friedreich ataxia are the most common lower motor neuron diseases causing disorders of the foot and lower extremities.
Charcot-Marie-Tooth (CMT), poliomyelitis, Roussy-Le´vy syndrome, and Friedreich ataxia are the most common lower motor neuron diseases causing disorders of the foot and lower extremities.
Sunday, September 13, 2015
MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia
T.A. Santos, C.E.B. Maistro, C.B. Silva, M.S. Oliveira, M.C. França Jr and G. Castellano; AJNR Am J Neuroradiol. Published online before print September 10, 2015, doi: 10.3174/ajnr.A4455
Gray level co-occurrence matrix–based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia.
Gray level co-occurrence matrix–based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia.
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