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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.

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia

Mounting evidence suggests that impairment in iron-sulfur cluster biosynthesis and iron accumulation in the mitochondria increase oxidative stress susceptibility and reactive oxygen species production in Friedreich's ataxia (FA). The FA pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here the authors provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.

Read the entire article HERE

Mechanisms of Mitochondrial Iron-Sulfur Protein Biogenesis

Work over the past two decades has uncovered the biogenesis of cellular iron-sulfur (Fe/S) proteins as the essential and minimal function of mitochondria. This process is catalyzed by the bacteria-derived iron-sulfur cluster assembly (ISC) machinery and has been dissected into three major steps: de novo synthesis of a [2Fe-2S] cluster on a scaffold protein; Hsp70 chaperone-mediated trafficking of the cluster and insertion into [2Fe-2S] target apoproteins; and catalytic conversion of the [2Fe-2S] into a [4Fe-4S] cluster and subsequent insertion into recipient apoproteins. ISC components of the first two steps are also required for biogenesis of numerous essential cytosolic and nuclear Fe/S proteins, explaining the essentiality of mitochondria. This review summarizes the molecular mechanisms underlying the ISC protein-mediated maturation of mitochondrial Fe/S proteins and the importance for human disease.

Read the entire article HERE

Developing an objective evaluating system to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia

The purpose of this study was to develop an easy-to-use application, for touchscreen devices, able to quantify the degree of upper limb movement impairment in patients with severe Friedreich's ataxia. The APP, which we named "Twelve-Red-Squares App-Coo-Test" (12-RSACT), assesses the upper limb ataxia by measuring the test execution time. All patients were clinically evaluated using the Composite Cerebellar Functional Severity (CCFS) and the Scale for the Assessment and Rating of Ataxia (SARA). 92 healthy subjects and 36 FRDA patients with a SARA mean value of 28.8.1 ± 8.2 were recruited. All participants in the study underwent upper limb movement assessment using the new 12-RSACT, the Click Test, and a well-established system, i.e., the Nine-Hole Peg Test (9HPT). A strong linear correlation between the measurements obtained with the 12-RSACT and those obtained with 9HPT, Click Test, CCFS, and SARA was observed. The 12-RSACT was characterized by excellent internal consistency and intra-rater and test-retest reliability. The minimal detectable change (MDC%) was excellent too. Additionally, the 12-RSACT turned out to be faster and easier to perform compared with the 9HPT. The 12-RSACT is an inexpensive test and is easy to use, which can be administered quickly. Therefore, 12-RSACT is a promising tool to assess the upper limb ataxia in FRDA patients and even those with severe diseases.

Read the entire article HERE

NfL and pNfH are increased in Friedreich's ataxia

The objective of this study was to assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia. Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia were performed and correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length was assessed. Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62). Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects, NfL levels were found to be stable.

Read the entire article HERE

Correlation of Visual Quality of Life With Clinical and Visual Status in Friedreich Ataxia

The primary objective of this study was to determine the association of patient-reported vision-specific quality of life to disease status and visual function in patients with Friedreich's ataxia (FRDA). Patients with FRDA were assessed with the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) along with measures of disease status (ataxia stage) and visual function (low- and high-contrast letter acuity scores). The relations of NEI-VFQ-25 scores to those for disease status and visual function were examined. Scores for the NEI-VFQ-25 were lower in patients with FRDA (n = 99) compared with published disease-free controls, particularly reduced in a subgroup of FRDA patients with features of early onset, older age, and abnormal visual function. The NEI-VFQ-25 captures the subjective component of visual function in patients with FRDA.

Read the entire article HERE

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