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FARAFARA Cure FA

 

FARA Funded Research

Your generous support has funded all the research listed below.


For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.

Mitochondrial dysfunction in neurons in Friedreich's ataxia

Based on clinical evidence, the peripheral nervous system is affected early in Friedreich's ataxia, neuronal dysfunction progresses towards the central nervous system, and other organs (such as heart and pancreas) are affected later. However, little attention has been given to the specific aspects of mitochondria function altered by frataxin depletion in the nervous system. For years, commonly accepted views on mitochondria dysfunction in Friedreich's ataxia stemmed from studies using non-neuronal systems and may not apply to neurons, which have their own bioenergetic needs and present a unique, extensive neurite network. Moreover, the basis of the selective neuronal vulnerability, which primarily affects large sensory neurons in the dorsal root ganglia, large principal neurons in the dentate nuclei of the cerebellum, and pyramidal neurons in the cerebral cortex, remains elusive. In order to identify potential misbeliefs in the field and highlight controversies, the authors reviewed current knowledge on frataxin expression in different tissues, discussed the molecular function of frataxin, and the consequences of its deficiency for mitochondria structural and functional properties, with a focus on the nervous system.

Read the entire article HERE

Orphan Drugs In Development For The Treatment Of Friedreich's Ataxia: Focus On Omaveloxolone

Nrf2 activators such as omaveloxolone (Omav) modulate antioxidative mechanisms, and thus may be viable therapeutic agents in Friedreich's Ataxia (FRDA). This paper reviews the MOXIe trial (NCT02255435, Reata Pharmaceuticals Inc) and the use of other Nrf2 activators as a viable option in the treatment of FRDA.

Read the entire article HERE

Temporal but not spatial dysmetria relates to disease severity in FA

Features of Friedreich's Ataxia (FA) include proprioceptive and cerebellar deficits leading to impaired muscle coordination and, consequently, dysmetria in force and time of movement. The aim of this study is to characterize dysmetria and its association to functional capacity. Also, the authors examine the neural mechanisms of dysmetria by quantifying the EMG burst area, duration, and time-to-peak of the agonist muscle. 27 individuals with FA and 13 healthy controls (HC) performed the modified Functional Ataxia Rating Scale (mFARS), and goal-directed movements with the ankle. Dysmetria was quantified as position and time error during dorsiflexion. FA individuals exhibited greater time but not position error than HC. Moreover, time error correlated with disease severity and was related to increased agonist EMG burst. Temporal dysmetria is associated to functional capacity, likely due to altered activation of the agonist muscle.

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.

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Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich's Ataxia

Primary neuronal cultures represent an essential tool in the study of events related to peripheral neuropathies as they allow to isolate the affected cell types, often originating in complex tissues in which they account for only a few percentage of cells. Neuronal cultures also provide a powerful system to identifying or testing compounds with potential therapeutic effect in the treatment of those diseases. Proprioceptive neurons of the dorsal root ganglia (DRG) are the primary affected cells in Friedreich's Ataxia. This paper describes a model of primary cultures of DRG sensory neurons in which there is an induced the loss of the frataxin protein. THis model can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. The authors provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.

Read the entire article HERE

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