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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.

Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. The authors first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested. In addition to SDH, five of the SDHIs, mostly from the latest generation, were shown to inhibit the activity of RC complex III. Finally, the authors demonstrated that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer's disease).

Read the entire article HERE

Speech and Language Disorders in Friedreich Ataxia: Highlights on Phenomenology, Assessment, and Therapy

Speech and language disorders are prominent signs in Friedreich ataxia (FRDA), which significantly impact on patients' quality of life. In this short review, the authors analyzed the existing literature to summarize what is known about the features of speech and language disorders in FRDA, which methods are used for evaluation and rating, and what are the available therapeutic strategies and future direction of scientific research in this field, in order to highlight critical aspects for a better clinical approach to the problem. FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease's biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.

Read the entire article HERE

The Structure of the Human ACP-ISD11 Heterodimer

In recent years the mammalian mitochondrial protein complex for iron-sulfur cluster assembly has been the focus of major studies. This is partly because of its high relevance in cell metabolism, but also because mutations of the involved proteins are the cause of several human diseases. Cysteine desulfurase NFS1 is the key enzyme of the complex. At present, it is well known that the active form of NFS1 is stabilized by the small protein ISD11. In this work, the structure of the human mitochondrial ACP-ISD11 heterodimer was solved at 2.0 Å resolution. ACP-ISD11 forms a cooperative unit stabilized by several ionic interactions, hydrogen bonds and also by apolar interactions. The 4'-phosphopantetheine-acyl chain, which is covalently bound to ACP, interacts with several residues of ISD11, modulating together with ACP the foldability of ISD11. Recombinant human ACP-ISD11 was able to interact with the NFS1 desulfurase, thus yielding an active enzyme, and the core complex NFS1/ACP-ISD11 was activated by frataxin and ISCU proteins. Internal motions of ACP-ISD11 were studied by molecular dynamic simulations, showing the persistence of the interactions between both protein chains. The conformation of the dimer is similar to the one found in the context of the supercomplex core (NFS1/ACP-ISD11)2, which contains the E. coli ACP instead of the human variant. This fact suggests a sequential mechanism for supercomplex consolidation, in which the ACP-ISD11 complex may fold independently and after that, the NFS1 dimer is stabilized.

Read the entire article HERE

Potential biomarker identification for Friedreich's ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion

To try to identify human Friedreich’s Ataxia (FA) biomarkers of neuro-pathomechanistic relevance, the authors compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, the goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted the investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which a significant change in FA patients was observed. These lead biomarkers that can be assayed in FA patient blood are believed to be indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

Read the entire article HERE

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. The authors report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene. The identified missense mutation has been reported previously in two Friedreich's ataxia (FRDA) cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from this family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. This family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that may have important implications on understanding the pathogenesis of these neurological disorders.

Read the entire article HERE

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