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FARAFARA Cure FA

 

Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

 


 

Deep sequencing of mitochondrial genomes reveals increased mutation load in Friedreich's ataxia

OBJECTIVE:
Friedreich's ataxia (FRDA) is an autosomal recessive trinucleotide repeat expansion disorder caused by epigenetic silencing of the frataxin gene (FXN). Current research suggests that damage and variation of mitochondrial DNA (mtDNA) contribute to the molecular pathogenesis of FRDA. We sought to establish the extent of the mutation burden across the mitochondrial genome in FRDA cells and investigate the molecular mechanisms connecting FXN downregulation and the acquisition of mtDNA damage.

METHODS:
Damage and mutation load in mtDNA of a panel of FRDA and control fibroblasts were determined using qPCR and next-generation MiSeq sequencing, respectively. The capacity of FRDA and control cells to repair oxidative lesions in their mtDNA was measured using a quantitative DNA damage assay. Comprehensive RNA sequencing gene expression analyses were conducted to assess the status of DNA repair and metabolism genes in FRDA cells.

Read the entire article HERE

Crystal Structure of Bacillus subtilis Cysteine Desulfurase SufS and Its Dynamic Interaction with Frataxin and Scaffold Protein SufU

The biosynthesis of iron sulfur (Fe-S) clusters in Bacillus subtilis is mediated by a SUF-type gene cluster, consisting of the cysteine desulfurase SufS, the scaffold protein SufU, and the putative chaperone complex SufB/SufC/SufD. Here, we present the high-resolution crystal structure of the SufS homodimer in its product-bound state (i.e., in complex with pyrodoxal-5'-phosphate, alanine, Cys361-persulfide). By performing hydrogen/deuterium exchange (H/DX) experiments, we characterized the interaction of SufS with SufU and demonstrate that SufU induces an opening of the active site pocket of SufS. Recent data indicate that frataxin could be involved in Fe-S cluster biosynthesis by facilitating iron incorporation. H/DX experiments show that frataxin indeed interacts with the SufS/SufU complex at the active site. Our findings deepen the current understanding of Fe-S cluster biosynthesis, a complex yet essential process, in the model organism B. subtilis.

Read the entire article HERE

Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and is associated with a number of potential outcomes, including impaired diastolic function, heart failure, and sudden cardiac death. Various etiologies have been described for HCM, including pressure overload and mutations in sarcomeric and non-sarcomeric genes. However, the molecular pathogenesis of HCM remains incompletely understood. In this study, we performed comparative transcriptome analysis to identify dysregulated genes common to five mouse HCM models of differing etiology: (i) mutation of myosin heavy chain 6, (ii) mutation of tropomyosin 1, (iii) expressing human phospholamban on a null background, (iv) knockout of frataxin, and (v) transverse aortic constriction. Gene-by-gene comparison identified five genes dysregulated in all five HCM models. Glutathione S-transferase kappa 1 (Gstk1) was significantly downregulated in the five models, whereas myosin heavy chain 7 (Myh7), connective tissue growth factor (Ctgf), periostin (Postn), and reticulon 4 (Rtn4) were significantly upregulated.

Read the entire article HERE

Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia

OBJECTIVE:
Although the diagnosis of inherited ataxias is ultimately genetic, this usually means an extensive and expensive process. This justifies the search for distinct clinical signs that may potentially help orient molecular diagnosis.

METHODS:
We explored the vestibulo-ocular reflex (VOR) with the video Head Impulse Test in patients diagnosed with spinocerebellar ataxia (SCA) type 3 (n = 15), type 1 (n = 4) and type 2 (n = 4), Friedreich's ataxia (FA) (n = 9) and healthy controls (n = 40). We estimated the latency, regression (VORr) and instantaneous VOR gain at 40, 60 and 80 ms (VOR40, VOR60 and VOR80), and determined the latency, peak-velocity and occurrence rate of catch-up saccades triggered with head-impulses.

Read the entire article HERE

Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

Mutations in Frataxin (FXN) cause Friedreich's ataxia (FRDA), a recessive neurodegenerative disorder. Previous studies have proposed that loss of FXN causes mitochondrial dysfunction, which triggers elevated reactive oxygen species (ROS) and leads to the demise of neurons. Here we describe a ROS independent mechanism that contributes to neurodegeneration in fly FXN mutants. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2). Dampening iron toxicity, inhibiting sphingolipid synthesis by Myriocin, or reducing Pdk1 or Mef2 levels, all effectively suppress neurodegeneration in fh mutants. Moreover, increasing dihydrosphingosine activates Mef2 activity through PDK1 in mammalian neuronal cell line suggesting that the mechanisms are evolutionarily conserved. Our results indicate that an iron/sphingolipid/PDk1/Mef2 pathway may play a role in FRDA.

Read the entire article HERE

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