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Review
. 2014 May 7:5:99.
doi: 10.3389/fphar.2014.00099. eCollection 2014.

Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms

Sonia Levi  1 , Dario Finazzi  2
Affiliations
Review

Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms

Sonia Levi et al. Front Pharmacol. .

Abstract

Perturbation of iron distribution is observed in many neurodegenerative disorders, including Alzheimer's and Parkinson's disease, but the comprehension of the metal role in the development and progression of such disorders is still very limited. The combination of more powerful brain imaging techniques and faster genomic DNA sequencing procedures has allowed the description of a set of genetic disorders characterized by a constant and often early accumulation of iron in specific brain regions and the identification of the associated genes; these disorders are now collectively included in the category of neurodegeneration with brain iron accumulation (NBIA). So far 10 different genetic forms have been described but this number is likely to increase in short time. Two forms are linked to mutations in genes directly involved in iron metabolism: neuroferritinopathy, associated to mutations in the FTL gene and aceruloplasminemia, where the ceruloplasmin gene product is defective. In the other forms the connection with iron metabolism is not evident at all and the genetic data let infer the involvement of other pathways: Pank2, Pla2G6, C19orf12, COASY, and FA2H genes seem to be related to lipid metabolism and to mitochondria functioning, WDR45 and ATP13A2 genes are implicated in lysosomal and autophagosome activity, while the C2orf37 gene encodes a nucleolar protein of unknown function. There is much hope in the scientific community that the study of the NBIA forms may provide important insight as to the link between brain iron metabolism and neurodegenerative mechanisms and eventually pave the way for new therapeutic avenues also for the more common neurodegenerative disorders. In this work, we will review the most recent findings in the molecular mechanisms underlining the most common forms of NBIA and analyze their possible link with brain iron metabolism.

Keywords: NBIA disorders; brain; iron; neurodegeneration; oxidative stress; pathogenesis.

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Figures

FIGURE 1
FIGURE 1
Pile up of the C-terminus amino acid sequences of L-ferritin and the mutants causing neuroferritinopathy. All mutations, localized in the exon 4 of FTL, are nucleotide insertions that cause large alterations of the C-terminal region of the subunit. This peptide portion forms the E-helix region, which is involved in the formation of the hydrophobic channel of the ferritin shell. Position of the A96T mutation is indicated by a blue arrow along the C-helix.
FIGURE 2
FIGURE 2
Scheme of pathogenetic molecular mechanism of neuroferritinopathy. The mutated peptide (green ellipse) assembles with the H- (red ellipse) and L- (blue ellipse) subunits to form ferritin shell, which is unable to incorporate iron properly. This leads to iron excess in the cytosol (cytLIP), which induces iron-dependent ferritin translation, generating a self-maintained vicious cycle, and at the same time stimulating ROS production and oxidative damage. In long period this causes impairment of the proteasome, ferritin aggregation, and cell death.
FIGURE 3
FIGURE 3
Schematic description of genes and biochemical pathways involved in different types of NBIA disorders. The biochemical pathways of lipid metabolism and membrane/organelles (mitochondria) remodeling seem to play an important mechanistic role in many of the genetic NBIA disorders so far identified.
FIGURE 4
FIGURE 4
Schematic representation of alteration of iron homeostasis control in PKAN fibroblasts. The scheme shows the different structural conformations of IRP1 (Apo, Fe–S, and mRNA-bound) in basal condition and after iron addition, in control (A) and in PKAN (B) cells. In basal condition, the amount of the regulatory functional form (mRNA-bound IRP1) is lower in PKAN than in controls fibroblasts. Controls cells respond to iron addition, reducing the amount of mRNA-bound IRP1 and leading to up-regulation of ferritin (Ft) and down-regulation of transferrin receptor 1 (TfR1). This does not occur in PKAN cells where the levels of Ft and TfR1 do not change allowing free iron increase.
FIGURE 5
FIGURE 5
Schematic representation of the different iPLA2-VIA isoforms. Group VI-1 is characterized by the presence of eight ankyrin repeats (red circles), a glycine-rich, nucleotide-binding motif (G), a consensus lipase motif (GXSXG), and a calmodulin binding motif (C). Group VI-2 has the insertion of a proline-rich motif (P) in place of the eighth ankyrin repeat. Group VI-3 has a truncated COOH-terminus but conserve the lipase motif while the ankyrin-1 and -2 lack the active site and are non-functional.
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