Neurodegeneration with brain iron accumulation: update on pathogenic mechanisms

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.

Contribution of metals to brain MR signal intensity: review articles

“…Although various factors other than iron content also affect the estimated iron concentration in the brain on MRI, MRI is used to diagnose many kinds of iron-storage diseases, such as neurodegeneration with brain iron accumulation (NBIA) [65][66][67][68], Alzheimer's disease [69,70], Parkinson's disease [71,72], multiple sclerosis [73,74], Friedreich's ataxia [75,76], and Huntington's disease [53,77]. NBIA is a group of neurodegenerative diseases characterized by iron accumulation in the basal ganglia.…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The incubation of ferritin with H 2 O 2 (Liu and Hu 2009), salsolinol (Kang 2009) or methylglyoxal and lysine (An and Kang 2013) caused oxidative DNA damage, and this was prevented by iron chelators. Furthermore the presence of mutant L ferritin with a perturbed COOH-terminal structure as observed in neuroferritinopathy patients leads to excess LIP and ROS generation (see also below) (Levi and Finazzi 2014). It is thus possible that, in specific chemical or genetic conditions, iron release from ferritin may be toxic to cells and tissues and contribute to the pathology.…”

“…The most paradigmatic example is Neuroferritinopathy (OMIM, 606159), an autosomal dominant neurodegenerative disorder due to mutations in the FtL gene and mainly characterized by extrapyramidal symptoms (McNeill and Chinnery 2012;Levi and Finazzi 2014). Magnetic resonance imaging reveals signs of cerebral iron accumulation, particularly in the basal ganglia (Crompton et al), and the histopathology confirmed the iron accumulation together with the presence of ferritin aggregates, with a nuclear or cytosolic localization, in neurons and glial cells; serum ferritin is often decreased (McNeill and Chinnery 2012).…”

“…The in vivo Barbeito et al 2009) and in vitro data (Cozzi et al 2006;Baraibar et al 2008) suggest that the mutant FtLs co-assemble with the endogenous ferritin and affect both iron loading and iron release. This would lead to a vicious cycle in which the augmented free iron pool would stimulate the synthesis of endogenous ferritin; the lack of a proper chelating capacity of the polymer would result in increased ROS generation, intensification in protein ubiquitination, proteasomal dysfunction and accumulation of ferritin aggregates (Levi and Finazzi 2014). The disorder is the most compelling evidence that perturbation of ferritin function and iron homeostasis may lead to neurodegeneration.…”

“…This is clearly suggested by the discovery that mutations in ferritin gene leads to Neuroferrintinopathy, a neurodegenerative disorder with brain iron accumulation. In particular, the study of in vitro and in vivo models of the disease have shown that the alteration of ferritin capacity to safely load and retain iron gives raise to excess free and redox-active iron, augmented oxidative damage, neuronal degeneration and death (Levi and Finazzi 2014). Whether similar processes may take place in other forms of sporadic neurodegenerative disorders is not clear yet, even though some indication are present in the literature.…”