Neurodegeneration in Friedreich's ataxia: from defective frataxin to oxidative stress

Abstract

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 the FXN gene 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 an α / β sandwich 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 the FXN coding 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.

Figure 1

Structures of the frataxin monomer and trimer, denoting the typical α/β fold in which the α-helices pack against the β-sheet strands. (a) Structure of the human frataxin monomer (PDB: 3S4M). (b) Structure of the yeast frataxin trimer (PDB: 3OEQ). Note that in the trimer structure, unwinding of the N-terminal α-helix affords an interaction with a β-sheet from the nearby subunit.

Figure 2

Mapping of amino acids mutated in FRDA compound heterozygous patients. FRDA mutations indicated on the human frataxin structure (PDB: 3S4M): Lys106Ser, Asp122Tyr, Gly130Val, Asn146Lys, Gln148Arg, Ile154Phe, Trp155Arg, Leu156Pro, Arg165Cys, Trp173Gly, Leu182Phe, Leu182His, and His183Arg. The arrow denotes a 90° rotation.