Wednesday, January 16, 2019

Young adult with Friedreich ataxia

Milano EG, Harries IB, Bucciarelli-Ducci C, Heart Published Online First: 15 January 2019. doi: 10.1136/heartjnl-2018-314387

Clinical introduction A young adult with Friedreich ataxia complaining of exertional breathlessness underwent a cardiological evaluation. On physical examination, high blood pressure and a loud systolic murmur were noted. ECG showed sinus rhythm with voltage criteria for left ventricular hypertrophy (LVH) and T-wave changes in the inferolateral leads. Transthoracic echocardiography showed biventricular hypertrophy (maximum wall thickness of the interventricular septum 26 mm and 16 mm of the posterior wall), preserved systolic function, mild left ventricular intracavity gradient and an unremarkable mitral and aortic valve. A cardiovascular magnetic resonance (CMR) was requested for further assessment. CMR protocol, performed using a 1.5 T scanner.

Tuesday, January 15, 2019

Revealing the Superpowers of PrimPol: rescuing replicating microsatellites

Reid, J. E., & Fischer, T. (2019). The EMBO Journal, e101298. doi:10.15252/embj.2018101298

Error‐free replication of repetitive stretches of DNA is crucial for human health, as more than 30 hereditary developmental and neurological diseases are linked to changes in length of microsatellites, where the repeating unit is < 9 nucleotides. Friedreich's ataxia (FRDA) is one such repeat expansion disease, exhibiting a large number of GAA repeats in the first intron of the FXN gene. Expansion of (GAA)n results in reduced levels of the FXN protein. Normal FXN alleles have < 12 repeats, while disease‐associated alleles often have 600–900 repeats. Therefore, it appears there is a limit to the number of (GAA)n repeats that can be present before this becomes damaging.

Monday, January 14, 2019

Ferroptosis as a novel therapeutic target for Friedreich's ataxia

M. Grazia Cotticelli, Shujuan Xia, Daniel Lin, Taehee Lee, Leila Terrab, Peter Wipf, Donna Huryn and Robert Wilson
Journal of Pharmacology and Experimental Therapeutics January 11, 2019, jpet.118.252759; DOI:10.1124/jpet.118.252759

Ferropotosis is a recently identified pathway of regulated, iron-dependent cell death, which is biochemically distinct from apoptosis. We evaluated whether there is evidence for ferroptotic pathway activation in cellular models of FRDA. We found that primary patient-derived fibroblasts, murine fibroblasts with FRDA-associated mutations, and murine fibroblasts in which a repeat expansion had been introduced (KIKO) were more sensitive than normal control cells to erastin, a known ferroptosis inducer. We also found that the ferroptosis inhibitors SRS11-92 and Fer-1, used at 500 nM, were efficacious in protecting human and mouse cellular models of FRDA treated with ferric ammonium citrate (FAC) and an inhibitor of glutathione synthesis (BSO), whereas caspase-3 inhibitors failed to show significant biological activity. Cells treated with FAC and BSO consistently showed decreased glutathione-dependent peroxidase activity and increased lipid peroxidation, both hallmarks of ferroptosis. Finally, the ferroptosis inhibitor SRS11-92 decreased the cell death associated with frataxin knockdown in healthy human fibroblasts. Taken together, these data suggest that ferroptosis inhibitors may have therapeutic potential in FRDA.

Sunday, January 13, 2019

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia

Phillip G. D. Ward PhD, Ian H. Harding PhD, Thomas G. Close PhD, Louise A. Corben PhD, Martin B. Delatycki MBBS, FRACP, PhD, Elsdon Storey DPhil
Nellie Georgiou‐Karistianis PhD, Gary F. Egan PhD; Movement Disorders : Official Journal of the Movement Disorder Society [09 Jan 2019] DOI: 10.1002/mds.27606

Progressive dentate nucleus abnormalities are 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 2‐year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool

Saturday, January 12, 2019

Etravirine in Friedreich's ataxia: Lessons from HIV?

Lynch DR, Schadt K1, Kichula E. Mov Disord. 2019 Jan 10. doi: 10.1002/mds.27605. [Epub ahead of print]

Friday, January 11, 2019

Drug repositioning screening identifies etravirine as a potential therapeutic for friedreich's ataxia

Giulia Alfedi MSc, Riccardo Luffarelli MSc, Ivano Condò PhD, Giorgia Pedini MSc, Liliana Mannucci PhD, Damiano S. Massaro PhD, Monica Benini PhD, Nicola Toschi PhD, Giorgia Alaimo PhD, Luca Panarello MSc, Laura Pacini PhD, Silvia Fortuni PhD, Dario Serio BS, Florence Malisan PhD, Roberto Testi MD, Alessandra Rufini PhD; Movement Disorders : Official Journal of the Movement Disorder Society [09 Jan 2019] Early View. DOI: 10.1002/mds.27604

Friedreich's ataxia is an autosomal-recessive cerebellar ataxia caused by mutation of the frataxin gene, resulting in decreased frataxin expression, mitochondrial dysfunction, and oxidative stress. Currently, no treatment is available for Friedreich's ataxia patients. Given that levels of residual frataxin critically affect disease severity, the main goal of a specific therapy for Friedreich's ataxia is to increase frataxin levels. With the aim to accelerate the development of a new therapy for Friedreich's ataxia, we took a drug repositioning approach to identify market-available drugs able to increase frataxin levels. Using a cell-based reporter assay to monitor variation in frataxin amount, we performed a high-throughput screening of a library containing 853 U.S. Food and Drug Administration-approved drugs. Among the potentially interesting candidates isolated from the screening, we focused our attention on etravirine, an antiviral drug currently in use as an anti-human immunodeficiency virus therapy. Here, we show that etravirine can promote a significant increase in frataxin levels in cells derived from Friedreich's ataxia patients, by enhancing frataxin messenger RNA translation. Importantly, frataxin accumulation in treated patient cell lines is comparable to frataxin levels in unaffected carrier cells, suggesting that etravirine could be therapeutically relevant. Indeed, etravirine treatment restores the activity of the iron-sulphur cluster containing enzyme aconitase and confers resistance to oxidative stress in cells derived from Friedreich's ataxia patients. Considering its excellent safety profile along with its ability to increase frataxin levels and correct some of the disease-related defects, etravirine represents a promising candidate as a therapeutic for Friedreich's ataxia.

Wednesday, January 2, 2019

Differences in the determinants of right ventricular and regional left ventricular long-axis dysfunction in Friedreich ataxia

Peverill RE, Donelan L, Corben LA, Delatycki MB (2018). PLoS ONE 13(12): e0209410. doi:10.1371/journal.pone.0209410

There are generalized abnormalities of RV and LV regional long axis function in FRDA, but there are also regional differences in the association of the various LV walls long-axis TDI velocities with the small and large alleles of the FXN gene and the extent of LV structural change. Further studies are required to confirm these findings and to investigate possible mechanisms which might explain these regional LV and RV differences.

Friday, December 28, 2018

GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models

Yi Na Dong Emily McMillian Elisia M Clark Hong Lin David R Lynch, Human Molecular Genetics, ddy448, doi:10.1093/hmg/ddy448 Published: 26 December 2018

We present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.

Monday, December 17, 2018

Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M. Gottesfeld, and Elisabetta Soragni; J. Biol. Chem. jbc.RA118.006515. doi:10.1074/jbc.RA118.006515

How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using “scarless” gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA•TTC repeats. To uncover the gene expression signatures due to the GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.

Saturday, December 15, 2018

Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms

Brahim Belbellaa, Laurence Reutenauer, Laurent Monassier, Hélène Puccio; Human Molecular Genetics, , ddy427, doi:10.1093/hmg/ddy427

Correlative analysis of vector cardiac biodistribution, survival, cardiac function and biochemical hallmarks of the disease revealed that full rescue of the cardiac function was achieved when only half of the cardiomyocytes were transduced. In addition, meaningful therapeutic effect was achieved with as little as 30% transduction coverage. This therapeutic effect was mediated through cell-autonomous mechanisms for mitochondria homeostasis, although a significant increase in survival of uncorrected neighboring cells was observed.