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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.

 


 

In Vitro interaction between yeast frataxin and superoxide dismutases: Influence of mitochondrial metals

Friedreich's ataxia results from a decreased expression of the nuclear gene encoding the mitochondrial protein, frataxin. Frataxin participates in the biosynthesis of iron-sulfur clusters and heme cofactors, as well as in iron storage and protection against oxidative stress. How frataxin interacts with the antioxidant defence components is poorly understood.This group investigated the molecular interactions between yeast frataxin (Yfh1) and superoxide dismutases, Sod1 and Sod2, and the influence of Yfh1 on their enzymatic activities using kinetic, thermodynamic and modelling approaches. They found that Yfh1 interacts with cytosolic Sod1 in two kinetic steps. The first step corresponds to the Yfh1-Sod1 interaction, whereas the second is assumed to be a change in the conformation of the protein-protein adduct. Furthermore, computational investigations confirm the stability of the Yfh1-Sod1 complex. Yfh1 forms two protein complexes with mitochondrial Sod2 with 1:1 and 2:1 Yfh1/Sod2 stoichiometry (Kd1 = 1.05 ± 0.05 and Kd2 = 6.6 ± 0.1 μM). Furthermore, Yfh1 increases the enzymatic activity of Sod1 while slightly affecting that of Sod2. Finally, the stabilities of the protein-protein adducts and the effect of Yfh1 on superoxide dismutase activities depend on the nature of the mitochondrial metal. This work confirms the participation of Yfh1 in cellular defense against oxidative stress.

Read the entire article HERE

The role of mitochondrial labile iron in Friedreich's ataxia skin fibroblasts sensitivity to ultraviolet A

Mitochondrial labile iron (LI) is a big factor in how sensitive skin cells are to ultraviolet A (UVA)-induced oxidative damage, which leads to cell death. Mitochondria iron overload is a key feature of FA. This group shows that cultured skin cells from FRDA patients are 4 to 10-fold more sensitive to UVA-induced death than their healthy counterparts. They show that FA cells have higher levels of mitochondrial LI (up to 6-fold on average compared to healthy counterparts) and show higher increase in mitochondrial reactive oxygen species (ROS) generation after UVA irradiation (up to 2-fold on average), consistent with their differential sensitivity to UVA. Pre-treatment of the FA cells with a bespoke mitochondrial iron chelator greatly reduces the UVA-mediated cell death and UVA-induced damage to the mitochondrial membrane. These results reveal a link between FA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. These findings suggest that the high levels of mitochondrial LI in FA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage.

Read the entire article HERE

Pattern of Cerebellar Atrophy in Friedreich's Ataxia-Using the SUIT Template

To date, imaging studies have revealed patterns of patchy atrophy within the cerebellum of Friedreich's ataxia patients, missing clear correlations between anatomical changes and changes in function. This group applied a high-resolution atlas template of the human cerebellum and brainstem (called the SUIT template) to characterize regional cerebellar atrophy in Friedreich's ataxia (FRDA). They looked at a representative cohort of 18 FRDA patients and matched healthy controls. They found that the cerebellar volume in FRDA is generally not significantly different from healthy controls but mild lobular atrophy develops beyond normal aging. The medial parts of lobule VI, housing the somatotopic representation of tongue and lips, are the major site of this lobular atrophy, which possibly reflects speech impairment. The degree of extended white matter correlates with disease severity across and beyond the cerebellar inflow and outflow tracts. The dentate nucleus, as a major site of cerebellar degeneration, shows a mean volume loss of about 30%. Remarkably, not the atrophy but the T2 signal decrease of the dentate nuclei highly correlates with disease duration and severity.

Read the entire article HERE

Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich's Ataxia Mouse Model

A major feature of FRDA is frataxin deficiency, with the loss of large sensory neurons of the dorsal root ganglia (DRG) undergoing dying-back neurodegeneration. This group used isolated DRGs from a FRDA mouse model and control mice for a proteomic study and a primary culture of sensory neurons from DRG to test novel pharmacological strategies. They found a decreased expression of electron transport chain proteins, the oxidative phosphorylation system and antioxidant enzymes, confirming a clear impairment in mitochondrial function and an oxidative stress-prone phenotype. The proteomic profile also showed a decreased expression in Ca2+ signaling related proteins and G protein-coupled receptors . These receptors modulate intracellular cAMP/cGMP and Ca2+ levels. Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons from YG8R mice. This suggests that PDE inhibitors should be looked at as a future FRDA treatment.

Read the entire article HERE

Heart disease in Friedreich's ataxia

Friedreich's ataxia (FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify. The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and (less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life. However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length (i.e., markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-users within 15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.

Read the entire article HERE

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