Iron in Neurodegeneration – Cause or Consequence?

Abstract

Iron dyshomeostasis can cause neuronal damage to iron-sensitive brain regions. Neurodegeneration with brain iron accumulation reflects a group of disorders caused by iron overload in the basal ganglia. High iron levels and iron related pathogenic triggers have also been implicated in sporadic neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple system atrophy (MSA). Iron-induced dyshomeostasis within vulnerable brain regions is still insufficiently understood. Here, we summarize the modes of action by which iron might act as primary or secondary disease trigger in neurodegenerative disorders. In addition, available treatment options targeting brain iron dysregulation and the use of iron as biomarker in prodromal stages are critically discussed to address the question of cause or consequence.

Iron, Ferritin, Hereditary Ferritinopathy, and Neurodegeneration

“…These lectures and texts generally focused on aggregation and fibrillization alone. However, the current literature is becoming increasingly clear concerning the very important connections between iron and AD, PD, Prion disease, motor neurone disease, and other chronic slowly-progressing neurodegenerative diseases (Biasiotto et al, 2015;Ndayisaba et al, 2019;Weiland et al, 2019). This review emphasizes the complexity of the cellular problem at hand with respect to interactions of iron with certain proteins and small molecules as caused by HF.…”

“…Such mechanisms are lysosomal and proteasomal ferritin degradation, and removal of iron through the ferritin three-fold pores, which have clearly been established as the entrance channels for iron but not as exit pathways. Current focus as the most likely and dominant iron release mechanism in normal cells is lysosomal degradation of ferritin through an autophagic process called ferritinophagy (Biasiotto et al, 2015;Ndayisaba et al, 2019), which is complicated and requires substantial cellular machinery, i.e., transport, synthesis and degradation. However, there is an extensive literature on completely different mechanisms (Crichton, 2009;DeDomenico et al, 2009;Bou-Abdallah et al, 2018), and it is not unreasonable to suggest that a fine tuned cell would have more than one way to remove iron from ferritin under different conditions, especially one that minimizes use of cellular material and energy and is not spatially dispersed.…”

Regulation of tissue iron homeostasis: the macrophage “ferrostat”

“…Central nervous system. Impaired iron homeostasis in the CNS is coupled with neuroinflammation, oxidative stress, neurodegenerative disease pathology, and cognitive decline (100)(101)(102)(103). Accordingly, iron must be tightly regulated on a cell-to-cell basis to ensure normal homeostatic function.…”

Brain iron transport

“…However, excess iron is a potent source of oxidative damage, through radical formation, to neuronal cells (Belaidi & Bush, 2016). Abnormally increased iron levels in the brain have been detected in various neurodegenerative diseases including neurodegeneration with brain iron accumulation (NBIA) (Rouault, 2013;Meyer, Kurian, & Hayflick, 2015;Ndayisaba, Kaindlstorfer, & Wenning, 2019), Alzheimer's disease (Ayton, Lei, & Bush, 2013;Raha et al, 2013;Belaidi & Bush, 2016), Parkinson's disease (Hare & Double, 2016;Liu, Liang, & Soong, 2019), Huntington's disease (Muller & Leavitt, 2014;Kwakye et al, 2019), and multiple sclerosis (Stephenson et al, 2014). In order to answer the key question of why iron levels increase abnormally in certain regions of the brain in some neurodegenerative disorders, considerable research effort has been devoted to understanding the mechanisms involved in brain iron homeostasis, and other physiological aspects of brain iron metabolism during recent decades.…”