Journal
NEUROBIOLOGY OF DISEASE
Volume 23, Issue 3, Pages 644-652Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2006.05.004
Keywords
hereditary ferritinopathy; ferritin; iron; oxidative stress
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Funding
- Telethon [GGP05141] Funding Source: Medline
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Hereditary ferritinopathies are dominant inherited movement disorders associated with extensive alterations of the L-ferritin C-terminus peptide caused by nucleotide insertions in L-ferritin gene (FTL). We describe the characterization of the most common variant, produced by the 460InsA mutations and here named Ln1. The recombinant Ln1 assembled into 24-mer ferritin shells with low efficiency, however, it was able to form heteropolymers that showed a reduced capacity to incorporate iron in vitro. The Ln1 expressed in HeLa cells formed hybrid ferritins, with the endogenous H and L chains, and caused an iron excess phenotype. Ferritin inactivation and faster degradation in Ln1 transfectants concurred in increasing iron availability, which was probably responsible for the higher sensitivity to H2O2 toxicity and higher level of oxidized proteins. The findings suggest that the pathogenic effects of Ln1 expression are more likely due to deregulation of cellular iron homeostasis rather than to protein conformational problems. (c) 2006 Elsevier Inc. All rights reserved.
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