Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

Figures & data

Figure 1. Iron labeling by DAB-enhanced Perls' staining in wildtype and Hfe^−/−xTfr2^mut mouse brain at 3 months of age. Iron is mainly accumulated in myelinated structures and associated cells. Myelin (M), oligodendrocyte (O), blood vessel (V) and black arrows show neurons (N) which do not accumulate appreciable iron even in the Hfe^−/−xTfr2^mut mouse brain.

Table 1. Myelin-related genes identified as differentially expressed in i. the Hfe^−/−xTfr2^mut mice in comparison with wildtype mice and ii. NBIA post-mortem basal ganglia samples compared to neurologically healthy control samples. FC: fold change. Asterisks indicate genes that were not reported as myelin-related genes in our previous paper.

Gene name and symbol	Function of encoded protein	Hfe^−/−xTfr2^mut FC (p value)	NBIA case 1	NBIA case 2
NBIA-related genes
Ferritin, light polypeptide Ftl	Iron storage	↑2.3 (0.0005)	–	–
Phospholipase A2, group VI Pla2g6	Fatty acid release from phospholipids	↓1.60 (0.010)	–	–
Fatty acid 2-hydroxylase Fa2h	2-hydroxy sphingolipid synthesis	↓1.41 (0.002)	–	–
*Ceruloplasmin Cp	Oxidation of Fe(II) to Fe(III), supports myelination in absence of hephaestin	↓1.35 (0.013)	–	–
Chromosome 19 open reading frame 12 C19orf12	Fatty acid biogenesis	↓1.28 (0.023)	–	–
ATPase type 13A2 Atp13a2	Ceramide synthesis in lysosomes, phospholipid distribution in myelin	↓1.17 S(0.047)	–	–
Myelin Structure and Biogenesis
*Hexose-6-phosphate dehydrogenase H6pd	Involved in NADPH production for myelin fatty acid synthesis, strongly enriched in oligodendrocytes	↓1.67 (0.0004)	–	–
Myelin-associated oligodendrocytic basic protein Mobp	Major myelin component, compacting and stabilizing the myelin sheath	↓1.48 (0.0004)	↓2.60	↓2.83
2′,3′-cyclic nucleotide 3′ phosphodiesterase Cnp	Major myelin component, hydrolyzes 2′,3′-cyclic nucleotides to 2′ derivatives	↓1.27 (0.0033)	–	–
Myelin oligodendrocyte glycoprotein Mog	Myelin surface component	↓1.14 (0.0398)	↑1.80	↑2.44
*Myelin-associated glycoprotein Mag	Myelin-axon interactions	↓1.13 (0.0301)	↑2.41	↑2.44
Sphingosine-1-phosphate phosphatase 2 Sgpp2	Catalyzes degradation of sphingosine-1-phosphate regenerating sphingosine	↓1.40 (0.0001)	↑1.91	↑2.06
Neutral sphingomyelinase (N-SMase) activation associated factor Nsmaf	Activation of neutral sphingomyelinase	↓1.34 (0.0142)	↑1.52	↑2.36
Sphingomyelin phosphodiesterase Smpd1	Converts sphingomyelin to ceramide	↓1.25 (0.0001)	↑2.40	–
*Prosaposin Psap	Sphingolipid activation	↓1.16 (0.0043)	↓1.82	↑1.57
*Cytochrome P450, family 51 Cyp51	Involved in cholesterol synthesis required for myelination	↓1.13 (0.0261)	–	–
Reticulon 4 RTN4	Myelin outgrowth inhibitor	↓1.33 (0.034)	–	–
Oligodendrocyte specific protein/claudin 11 Cldn11	Myelin compaction	↓1.13 (0.0127)	–	–
Gap junction protein, gamma 2 Gjc2	Gap junction protein with roles in myelination, mutation causes progressive leukodystrophy	↓1.27 (0.0052)	↓2.47	↓2.87
Tetraspanin 2 Tspan2	Involved in oligodendrocyte differentiation to generate myelin, stabilizes myelin	↓1.22 (0.0238)	–	–
*Heat shock 60 kDa protein 1 Hspd1	Involved in myelin development, mutation causes hypomyelinating leukodystrophy	↓1.31 (0.0004)	–	↓2.01
*Annexin A2 Anxa2	Involved in paranodal regions in peripheral myelin, induces membrane budding and lipid segregation	↓1.11 (0.0184)	↑1.70	↑1.60
*Multiple PDZ domain protein Mpdz	Involved in oligodendrocyte-astrocyte gap junctions and tight junctions in myelinating Schwann cells	↓1.16 (0.0229)	–	↑1.62
*Exocyst complex component 4 Exoc4	Regulates transport of myelin proteins to site of membrane growth in oligodendrocytes and Schwann cells	↓1.16 (0.0464)	–	–
*Aldo-keto reductase family 1, member B1 Akr1b1	Present in myelin, catalyzes NADPH-dependent reduction of glucose to sorbitol, implicated in diabetic neuropathy	↑1.20 (0.0111)	–	–
Other myelin-related functions
*Klotho Kl	Enhances oligodendrocyte maturation and myelination	↓1.38 (0.0003)	–	–
Transferrin Tf	Iron transport and Mbp transcription regulator	↓1.33 (0.00002)	–	↑1.98
*Solute carrier family 12, member 6 Slc12a6	Myelin development, mutation causes agenesis of the corpus callosum	↓1.29 (0.0180)	–	–
Histamine receptor H3 Hrh3	Myelin component, involved in experimental autoimmune encephalomyelitis (EAE) development	↓1.25 (0.041)	–	–
Ring finger protein 10 Rnf10	Transcriptional regulation of the myelin-associated glycoprotein gene	↓1.21 (0.0448)	↑1.91	–
Tumor necrosis factor receptor superfamily, member 21 Tnfrsf21	Negatively regulates oligodendrocyte survival, maturation and myelination	↓1.50 (0.0029)	↓4.25	↓1.85
Leucine rich repeat and Ig domain containing 1 Lingo1	Negatively regulates myelination	↓1.20 (0.0169)	–	–
*Myotubularin related protein 2 Mtmr2	Negatively regulates membrane formation in Schwann cells, linked to Charcot-Marie-Tooth disease type 4B1	↓1.19 (0.0489)	↓1.58	–
*Superoxide dismutase 1, soluble Sod1	Oligodendrocyte maturation, linked to amyotrophic lateral sclerosis	↑1.12 (0.0366)	↓2.31	↑1.52
*Beta-site APP-cleaving enzyme 1 Bace1	Enhances myelination, cleaves the amyloid precursor protein at the β-secretase site	↓1.10 (0.0117)	–	–
*Kallikrein-related peptidase 8 Klk8	Demyelination and oligodendrocyte death in experimental allergic encephalomyelitis (EAE) is attenuated in Klk8 knockouts	↑1.22 (0.0183)	–	–
Ganglioside induced differentiation associated protein 1 Gdap1	Mitochondrial fission factor, Gdap1-knockouts develop hypomyelinating peripheral neuropathy	↓1.12 (0.0380)	–	–
*Fibroblast growth factor receptor 3 Fgfr3	Regulates oligodendrocyte terminal differentiation and timing of myelination, regulates injury-related effects in the peripheral nervous system	↓1.27 (0.0382)	–	↓6.24
*Neurotrophic tyrosine kinase, receptor, type 2 Trkb	Regulates CNS myelination and progenitor cell proliferation through its ligand, brain derived neurotrophic factor (BDNF)	↓1.16 (0.0331)	–	–
*SRY (sex determining region Y)-box 17 Sox17	Regulates oligodendrocyte progenitor cell cycle exit and differentiation, oligodendrocyte survival	↓1.74 (0.0426)	–	–

Table 2. Some important myelin-related genes identified as differentially expressed in NBIA post-mortem basal ganglia samples compared to neurologically healthy control samples (asterisks indicate newly identified genes).

Gene name and symbol	NBIA case 1	NBIA case 2
NBIA-related genes
*Pantothenate kinase 2 PANK2	↓3.80	↑1.56
*WD repeat domain 4 WDR45	↑1.99	↑1.56
Myelin Structure and Biogenesis
Myelin basic protein MBP	↑2.33	↑1.82
*Mal T-cell differentiation protein MAL	↑1.94	↑3.23
Oligodendrocyte myelin glycoprotein OMG	↑1.89	↑2.35
*Proteolipid protein 1 PLP1	–	↑4.1
Other myelin-related functions
Oligodendrocytic myelin paranodal and inner loop protein OPALIN	↑2.70	↑3.30
*Dicer 1 ribonuclease III DICER1	↑2.53	↑3.51 ↓1.68
*B-cell CLL/lymphoma 2 BCL2	↑2.52	–
*Achaete-scute family bHLH transcription factor 1 ASCL1	↑2.30	–
*Niemann-Pick disease, type C1 NPC1	↑2.13	↑4.08
Peripheral myelin protein 2 PMP2	–	↑1.61
Myelin transcription factor 1 MYT1	–	↓3.70