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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.


Relationship between activity and stability: Design and characterization of stable variants of human frataxin

Frataxin (FXN) is an essential protein that forms part of a supercomplex dedicated to the iron-sulfur (Fe-S) cluster assembly within the mitochondrial matrix. Recently, the way in which FXN interacts with the rest of the subunits of the supercomplex was uncovered. This opens a window to explore relationships between structural dynamics and function. In this study, the authors prepared a set of FXN variants spanning a broad range of conformational stabilities. Variants S160I, S160 M and A204R were more stable than the wild-type and showed similar biological activity. Additionally, we prepared SILCAR, a variant that combines S160I, L203C and A204R mutations. SILCAR was 2.4 kcal mol-1 more stable and equally active. Some of the variants were significantly more resistant to proteolysis than the wild-type FXN. SILCAR showed the highest resistance, suggesting a more rigid structure. It was corroborated by means of molecular dynamics simulations. Relaxation dispersion NMR experiments comparing SILCAR and wild-type variants suggested similar internal motions in the microsecond to millisecond timescale. Instead, variant S157I showed higher denaturation resistance but a significant lower function, similarly to that observed for the FRDA variant N146K. The authors concluded that the contribution of particular side chains to the conformational stability of FXN might be highly subordinated to their impact on both the protein function and the stability of the functional supercomplex.

Read the entire article HERE

Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, the authors provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer's, Parkinson's, Huntington's, Amyotrophic Lateral Sclerosis, Friedreich's Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. This review also discusses the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.

Read the entire article HERE

Safety and Efficacy of (+)-Epicatechin in Subjects with Friedreich's Ataxia: A Phase II, Open-Label, Prospective Study

(+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. The authors aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's Ataxia (FRDA). This Phase II, open-label, baseline-controlled single-center trial included ten participants ages 10-22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/day for 24 weeks, with escalation to 150 mg/day at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac MRI and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. Mean FARS/modified (m)FARS scores showed non-statistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = 0.045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = 0.008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = 0.031). There were no serious adverse events. (+)-EPI was well tolerated over 24 weeks at up to 150 mg/day. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes.

Read the entire article HERE

MR imaging and spectroscopy in degenerative ataxias: toward multimodal, multisite, multistage monitoring of neurodegeneration

Degenerative ataxias are rare and currently untreatable movement disorders, primarily characterized by neurodegeneration in the cerebellum and brainstem. The authors highlight MRI studies with the most potential for utility in pending ataxia trials and underscore advances in disease characterization and diagnostics in the field. With availability of advanced MRI acquisition methods and specialized software dedicated to the analysis of MRI of the cerebellum, patterns of cerebellar atrophy in different degenerative ataxias are increasingly well defined. The field further embraced rigorous multimodal investigations to study network-level microstructural and functional brain changes and their neurochemical correlates. MRI and magnetic resonance spectroscopy were shown to be more sensitive to disease progression than clinical scales and to detect abnormalities in premanifest mutation carriers. Magnetic resonance techniques are increasingly well placed for characterizing the expression and progression of degenerative ataxias. The most impactful work has arguably come through multi-institutional studies that monitor relatively large cohorts, multimodal investigations that assess the sensitivity of different measures and their interrelationships, and novel imaging approaches that are targeted to known pathophysiology (e.g., iron and spinal imaging in Friedreich ataxia). These multimodal, multi-institutional studies are paving the way to clinical trial readiness and enhanced understanding of disease in degenerative ataxias.

Read the entire article HERE

Cardiolipin-deficient cells have decreased levels of the iron-sulfur biogenesis protein frataxin

Cardiolipin (CL) is the signature phospholipid of mitochondrial membranes, where it is synthesized locally and plays an important role in mitochondrial bioenergetics. Previous studies in the yeast model have indicated that CL is required for optimal iron homeostasis, which is disrupted by a mechanism not yet determined in the yeast CL mutant, crd1Δ. This finding has implications for the severe genetic disorder, Barth syndrome (BTHS), in which CL metabolism is perturbed because of mutations in the CL-remodeling enzyme, tafazzin. Here, we investigate the effects of tafazzin-deficiency on iron homeostasis in the mouse myoblast model of BTHS, TAZ-KO (tafazzin knockout) cells. Similarly to CL-deficient yeast cells, TAZ-KO cells exhibited elevated sensitivity to iron as well as to H2O2, which was alleviated by the iron chelator deferoxamine. TAZ-KO cells exhibited increased expression of the iron exporter ferroportin and decreased expression of the iron importer transferrin receptor, likely reflecting a regulatory response to elevated mitochondrial iron. Reduced activities of mitochondrial iron-sulfur cluster (Fe-S) enzymes suggested that the mechanism underlying perturbation of iron homeostasis was defective Fe-S biogenesis. This study showed decreased levels of Yfh1/frataxin, an essential component of the Fe-S biogenesis machinery, in mitochondria from TAZ-KO mouse cells and in CL-deleted yeast crd1Δ cells, indicating that the role of CL in Fe-S biogenesis is highly conserved. Yeast crd1Δ cells exhibited decreased processing of the Yfh1 precursor upon import, which likely contributes to the iron homeostasis defects. Implications for understanding the pathogenesis of BTHS are discussed.

Read the entire article HERE

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