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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.



Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

Mootha lab team Frataxin participates in the biosynthesis of Fe-S clusters and is considered to be essential for viability. This paper reports that when grown in 1% ambient O2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O2 attenuates the progression of ataxia, whereas breathing 55% O2 hastens it. This work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

Read the entire article HERE

Download the Q&A PDF HERE

Probing the multifactorial source of hand dysfunction in Friedreich ataxia

Friedreich ataxia (FRDA) has a significant effect on hand function which in turn, may compromise independence and quality of life. This study sought to identify the extent of muscle weakness, spasticity and changes in joint range in the hands of individuals with FRDA. The group found evidence for both upper and lower motor neuron impairment in this population. Thirteen (68.0%) participants had spasticity in the dominant wrist and finger flexors, and seven (36.8%) had contracture in at least one joint of either hand. Sixteen (84.3%) participants demonstrated weakness in the intrinsic musculature of the hands and the majority demonstrated some degree of hyperextension at the metacarpophalangeal joints of either hand. Significant correlations were found between functional independence capacity and clinical parameters, and components of spasticity and weakness in both the dominant and non-dominant hands. Moreover, spasticity and weakness in the dominant hand were shown to be significant predictors of reduced functional independence capacity. This study highlights for the first time the incidence of upper limb spasticity which, in combination with weakness and contracture, suggests a multifactorial source of hand dysfunction in people with FRDA.

Read the entire article HERE

Identification of a novel missense mutation in Friedreich's ataxia -FXNW 168R

Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, the authors find that frataxinW168R, a novel disease-causing missense mutation, is expressed predominantly as the intermediate frataxin42-210 form, with very little expression of mature frataxin81-210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease-modifying manner.

Read the entire article HERE

Mechanism of frataxin "bypass" in human iron-sulfur cluster biosynthesis with implications for Friedreich's ataxia

In humans, mitochondrial iron-sulfur (Fe-S) cluster biosynthesis is an essential process mediated by the assembly complex. The protein frataxin (FXN) is an allosteric activator that binds the assembly complex and stimulates the assembly activities. FXN depletion causes loss of activity of Fe-S-dependent enzymes and the development of the neurodegenerative disease Friedreich's ataxia. Recently, a mutation that suppressed the loss of the FXN homolog in yeast was identified that encodes an amino acid substitution equivalent to the human variant ISCU2 M140I. Here, we developed Fe-S cluster synthesis and transfer functional assays and determined that the human ISCU2 M140I variant can substitute for FXN in accelerating the rate of Fe-S cluster formation. Incorporation of both FXN and the M140I substitution had an additive effect, suggesting an acceleration of distinct steps in Fe-S cluster biogenesis. In contrast to the canonical role of FXN in stimulating the formation of [2Fe-2S]-ISCU2 intermediates, we found here that the M140I substitution in ISCU2 promotes the transfer of Fe-S clusters to GRX5. Together, these results reveal an unexpected mechanism that replaces FXN-based stimulation of the Fe-S cluster biosynthetic pathway and suggest new strategies to overcome the loss of cellular FXN that may be relevant to the development of therapeutics for Friedreich's ataxia.

Read the entire article HERE

Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich Ataxia

In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-γ 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-γ 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial. Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-γ 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open-label extension period, subjects had a more stable course than expected based on natural history data. This study provides no direct evidence for a beneficial effect of IFN-γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

Read the entire article HERE

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