Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes.

Keywords: NBIA; Tau; autophagy; mitochondria; neurodegeneration; α-synuclein.

Figure 1

Cellular localization of NBIA‐associated genes. Iron (black circles) is taken up via transferrin‐mediated endocytosis (upper right). Cytoplasmic iron is stored in ferritin, made up of 24 monomers of ferritin light chain (FTL) and ferritin heavy chain. GPI‐anchored Ceruloplasmin (CP) facilitates Transferrin‐mediated cellular export of iron. Free CP is also present in serum. Mitochondria and lysosomes contain most of the total cellular iron. Pantothenate kinase 2 (PANK2) is a dimer and localized to intermembrane space of the mitochondria. CoA Synthase (COASY) and C19orf12 are currently believed to reside in the inner mitochondrial membrane and the outer mitochondrial membrane, respectively. COASY has a single transmembrane domain, and C19orf12 has two membrane spanning domains. Phospholipase A2 G6 (PLA2G6) is a cytoplasmic tetramer that, upon activation, can be oleoylated and associated to the plasma membrane, mitochondrial membranes, endoplasmic reticulum (ER) and nuclear envelope. WDR45 is a seven bladed β‐propeller protein that binds to phosphoinositol‐3‐phosphate‐enriched membranes at the ER. Fatty acid hydroxylase 2 (FA2H) is a four‐pass protein located in the ER. ATP13A2 is a 10‐pass polypeptide that resides in the lysosomal compartment (dark vesicles) and possibly the mitochondrial inner membrane. Finally, DCAF17 is a single pass protein located in the nucleolus.

Figure 2

Cellular iron homeostasis and putative involvement of NBIA‐associated genes. Iron is taken up via transferrin‐mediated endocytosis and a theorized cytoplasmic pool of free iron is termed the LIP. Free iron is safely stored within Ferritin macromolecules, via Ferritin heavy chain and FTH. Cellular iron export is facilitated via the ferroxidase activity of Ceruloplasmin. High iron concentration is required in mitochondria; however, no mitochondrial iron exporter has been found. Mitophagy is one potential mechanism for iron recycling, and several NBIA‐related genes may alter the rate of mitophagy, PANK2, COASY, C19orf12 and PLA2G6. Autophagy and mitophagy are intrinsically related, and WDR45 mutations may alter the rate of these recycling processes. FA2H and PLA2G6 may impinge on autophagy via membrane remodelling and vesicle formation. ATP13A2 has a role in divalent ion transport into the lysosome compartment, and this could include/affect iron transport into the iron‐rich lysosomal compartment. DCAF17 has not been linked to iron homeostasis. Mitochondrial‐rich vesicles have been described to be exocytosed and, together with theorized lysosomal‐derived exosomes, may represent another cellular iron secretory mechanism. Grey arrows represent theorized steps in the pathway. Black circles represent iron.