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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.

 


 

Guidelines on the diagnosis and management of the progressive ataxias

The progressive ataxias are a group of rare and complicated neurological disorders, knowledge of which is often poor among healthcare professionals (HCPs). The patient support group Ataxia UK, recognising the lack of awareness of this group of conditions, has developed medical guidelines for the diagnosis and management of ataxia. Although ataxia can be a symptom of many common conditions, the focus here is on the progressive ataxias, and include hereditary ataxia (e.g. spinocerebellar ataxia (SCA), Friedreich's ataxia (FRDA)), idiopathic sporadic cerebellar ataxia, and specific neurodegenerative disorders in which ataxia is the dominant symptom (e.g. cerebellar variant of multiple systems atrophy (MSA-C)). Over 100 different disorders can lead to ataxia, so diagnosis can be challenging. Although there are no disease-modifying treatments for most of these entities, many aspects of the conditions are treatable, and their identification by HCPs is vital. The early diagnosis and management of the (currently) few reversible causes are also of paramount importance. More than 30 UK health professionals with experience in the field contributed to the guidelines, their input reflecting their respective clinical expertise in various aspects of ataxia diagnosis and management. They reviewed the published literature in their fields, and provided summaries on "best" practice, including the grading of evidence available for interventions, using the Guideline International Network (GIN) criteria, in the relevant sections.A Guideline Development Group, consisting of ataxia specialist neurologists and representatives of Ataxia UK (including patients and carers), reviewed all sections, produced recommendations with levels of evidence, and discussed modifications (where necessary) with contributors until consensus was reached. Where no specific published data existed, recommendations were based on data related to similar conditions (e.g. multiple sclerosis) and/or expert opinion. The guidelines aim to assist HCPs when caring for patients with progressive ataxia, indicate evidence-based (where it exists) and best practice, and act overall as a useful resource for clinicians involved in managing ataxic patients. They do, however, also highlight the urgent need to develop effective disease-modifying treatments, and, given the large number of recommendations based on "good practice points", emphasise the need for further research to provide evidence for effective symptomatic therapies.These guidelines are aimed predominantly at HCPs in secondary care (such as general neurologists, clinical geneticists, physiotherapists, speech and language therapists, occupational therapists, etc.) who provide care for individuals with progressive ataxia and their families, and not ataxia specialists. It is a useful, practical tool to forward to HCPs at the time referrals are made for on-going care, for example in the community.

Read the entire article HERE

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

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