Deficiency of Calcium-Independent Phospholipase A2 Beta Induces Brain Iron Accumulation through Upregulation of Divalent Metal Transporter 1.
Mutations in PLA2G6 have been proposed to be the cause of neurodegeneration with brain iron accumulation type 2. The present study aimed to clarify the mechanism underlying brain iron accumulation during the deficiency of calcium-independent phospholipase A2 beta (iPLA2β), which is encoded by the PLA2G6 gene. Perl's staining with diaminobenzidine enhancement was used to visualize brain iron accumulation. Western blotting was used to investigate the expression of molecules involved in iron homeostasis, including divalent metal transporter 1 (DMT1) and iron regulatory proteins (IRP1 and 2), in the brains of iPLA2β-knockout (KO) mice as well as in PLA2G6-knockdown (KD) SH-SY5Y human neuroblastoma cells. Furthermore, mitochondrial functions such as ATP production were examined. We have discovered for the first time that marked iron deposition was observed in the brains of iPLA2β-KO mice since the early clinical stages. DMT1 and IRP2 were markedly upregulated in all examined brain regions of aged iPLA2β-KO mice compared to age-matched wild-type control mice. Moreover, peroxidized lipids were increased in the brains of iPLA2β-KO mice. DMT1 and IRPs were significantly upregulated in PLA2G6-KD cells compared with cells treated with negative control siRNA. Degeneration of the mitochondrial inner membrane and decrease of ATP production were observed in PLA2G6-KD cells. These results suggest that the genetic ablation of iPLA2β increased iron uptake in the brain through the activation of IRP2 and upregulation of DMT1, which may be associated with mitochondrial dysfunction.
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Goichi
G
Beck
Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Koei
K
Shinzawa
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hideki
H
Hayakawa
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Kousuke
K
Baba
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Human Genetics, National Center for Child Health and Development, Tokyo, Japan.
Toru
T
Yasuda
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hisae
H
Sumi-Akamaru
Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
Yoshihide
Y
Tsujimoto
Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hideki
H
Mochizuki
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D054522:Group VI Phospholipases A2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D015533:Transcriptional Activation; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D054522:Group VI Phospholipases A2; D007501:Iron; D035942:Iron Regulatory Protein 2; D000099236:Solute Carrier Family 11, Member 2; C535117:Pla2g6 protein, rat