Anomalies of Form and Function in Friedreich's Ataxia

Friedreich’s ataxia is the most common inherited autosomal recessive ataxia and is characterized by progressive degeneration of the peripheral and central nervous systems and cardiomyopathy. This disease is caused by the silencing of theFXNgene and reduced levels of the encoded protein, frataxin. Frataxin is a mitochondrial protein that functions primarily in iron-sulfur cluster synthesis. This small protein with anα/βsandwich fold undergoes complex processing and imports into the mitochondria, generating isoforms with distinct N-terminal lengths which may underlie different functionalities, also in respect to oligomerization. Missense mutations in theFXNcoding region, which compromise protein folding, stability, and function, are found in 4% of FRDA heterozygous patients and are useful to understand how loss of functional frataxin impacts on FRDA physiopathology. In cells, frataxin deficiency leads to pleiotropic phenotypes, including deregulation of iron homeostasis and increased oxidative stress. Increasing amount of data suggest that oxidative stress contributes to neurodegeneration in Friedreich’s ataxia.

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Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich’s Ataxia

Antioxidants ◽

10.3390/antiox9121257 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1257

Author(s):

Marta Seco-Cervera ◽

Pilar González-Cabo ◽

Federico Pallardó ◽

Carlos Romá-Mateo ◽

José García-Giménez

Keyword(s):

Transcriptional Control ◽

Extracellular Fluid ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Special Role ◽

Cellular Processes ◽

Expression Of Genes ◽

Iron Response Element ◽

New Treatments ◽

And Function

The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.

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INFLUENCE OF GENETIC FACTORS ON LEFT VENTRICULAR STRUCTURE AND FUNCTION IN FRIEDREICH’S ATAXIA

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(10)60260-4 ◽

2010 ◽

Vol 55 (10) ◽

pp. A27.E259

Author(s):

Sarah Lagedrost ◽

Ted Plappert ◽

Martin St John Sutton ◽

David Lynch

Keyword(s):

Genetic Factors ◽

Friedreich’S Ataxia ◽

Left Ventricular ◽

Structure And Function ◽

Friedreich's Ataxia ◽

Left Ventricular Structure ◽

Ventricular Structure ◽

And Function

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Scanning tunneling microscopy (STM) of DNA and RNA

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100152148 ◽

1989 ◽

Vol 47 ◽

pp. 34-35

Author(s):

Patricia G. Arscott ◽

Gil Lee ◽

Victor A. Bloomfield ◽

D. Fennell Evans

Keyword(s):

Molecular Structures ◽

Inorganic Materials ◽

Resolving Power ◽

Scanning Tunneling ◽

Tunneling Microscopy ◽

Form And Function ◽

Dna And Rna ◽

Calf Thymus ◽

And Function ◽

The Relationship

STM is one of the most promising techniques available for visualizing the fine details of biomolecular structure. It has been used to map the surface topography of inorganic materials in atomic dimensions, and thus has the resolving power not only to determine the conformation of small molecules but to distinguish site-specific features within a molecule. That level of detail is of critical importance in understanding the relationship between form and function in biological systems. The size, shape, and accessibility of molecular structures can be determined much more accurately by STM than by electron microscopy since no staining, shadowing or labeling with heavy metals is required, and there is no exposure to damaging radiation by electrons. Crystallography and most other physical techniques do not give information about individual molecules.We have obtained striking images of DNA and RNA, using calf thymus DNA and two synthetic polynucleotides, poly(dG-me5dC)·poly(dG-me5dC) and poly(rA)·poly(rU).

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