Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation
WANG Xiao-Su, JIANG Li
Department of Neurology, Children's Hospital of Chongqing Medical University/National Clinical Research Center for Child Health and Disorders/Ministry of Education Key Laboratory of Child Development and Disorders/Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China
Abstract Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic degenerative diseases caused by genetic mutations and characterized by iron deposition in the central nervous system, especially in the basal ganglia, with an overall incidence rate of 2/1 000 000-3/1 000 000. Major clinical manifestations are extrapyramidal symptoms. This disease is presently classified into 14 different subtypes based on different pathogenic genes, and its pathogenesis and treatment remain unclear. This article summarizes the research advances in the pathogenesis and treatment of NBIA, so as to help pediatricians understand this disease and provide a reference for subsequent research on treatment.
WANG Xiao-Su,JIANG Li. Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation[J]. CJCP, 2021, 23(6): 650-656.
WANG Xiao-Su,JIANG Li. Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation[J]. CJCP, 2021, 23(6): 650-656.
Hallervorden J, Spatz H. Eigenartige erkrankung im extrapyramidalen system mit besonderer beteiligung des globus pallidus und der substantia nigra[J]. Zeitschrift für die gesamte Neurologie und Psychiatrie, 1922, 79(1):254-302. DOI:10.1007/BF02878455.
[2]
Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome[J]. Nat Genet, 2001, 28(4):345-349. DOI:10.1038/ng572. PMID:11479594.
[3]
Hayflick SJ. Unraveling the Hallervorden-Spatz syndrome:pantothenate kinase-associated neurodegeneration is the name[J]. Curr Opin Pediatr, 2003, 15(6):572-577. DOI:10.1097/00008480-200312000-00005. PMID:14631201.
[4]
Levi S, Cozzi A, Santambrogio P. Iron pathophysiology in neurodegeneration with brain iron accumulation[J]. Adv Exp Med Biol, 2019, 1173:153-177. DOI:10.1007/978-981-13-9589-5_9. PMID:31456210.
[5]
Dusi S, Valletta L, Haack TB, et al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation[J]. Am J Hum Genet, 2014, 94(1):11-22. DOI:10.1016/j.ajhg.2013.11.008. PMID:24360804.
[6]
Delgado RF, Sanchez PR, Speckter H, et al. Missense PANK2 mutation without "eye of the tiger" sign:MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN)[J]. J Magn Reson Imaging, 2012, 35(4):788-794. DOI:10.1002/jmri.22884. PMID:22127788.
[7]
Schneider SA. Neurodegeneration with brain iron accumulation[J]. Curr Neurol Neurosci Rep, 2016, 16(1):9. DOI:10.1007/s11910-015-0608-3. PMID:26739693.
[8]
Jeong SY, Hogarth P, Placzek A, et al. 4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN[J]. EMBO Mol Med, 2019, 11(12):e10489. DOI:10.15252/emmm.201910489. PMID:31660701.
[9]
Pagani F, Trivedi A, Khatri D, et al. Silencing of pantothenate kinase 2 reduces endothelial cell angiogenesis[J]. Mol Med Rep, 2018, 18(5):4739-4746. DOI:10.3892/mmr.2018.9480. PMID:30221726.
[10]
Werning M, Müllner EW, Mlynek G, et al. PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes[J]. Ann Clin Transl Neurol, 2020, 7(8):1340-1351. DOI:10.1002/acn3.51127. PMID:32705819.
[11]
Chang CL, Lin CM. Eye-of-the-tiger sign is not pathognomonic of pantothenate kinase-associated neurodegeneration in adult cases[J]. Brain Behav, 2011, 1(1):55-56. DOI:10.1002/brb3.8. PMID:22398981.
[12]
Parmar A, Khare S, Srivastav V. Pantothenate-kinase associated neurodegeneration[J]. J Assoc Physicians India, 2012, 60:74-76. PMID:23029753.
[13]
Ley Martos M, Salado Reyes MJ, Marín Iglesias R, et al. A new allelic variant in the PANK2 gene in a patient with incomplete HARP syndrome[J]. J Mov Disord, 2020, 13(3):229-231. DOI:10.14802/jmd.19071. PMID:32654475.
[14]
Sharma LK, Subramanian C, Yun MK, et al. A therapeutic approach to pantothenate kinase associated neurodegeneration[J]. Nat Commun, 2018, 9(1):4399. DOI:10.1038/s41467-018-06703-2. PMID:30352999.
[15]
Lambrechts RA, Schepers H, Yu Y, et al. CoA-dependent activation of mitochondrial acyl carrier protein links four neurodegenerative diseases[J]. EMBO Mol Med, 2019, 11(12):e10488. DOI:10.15252/emmm.201910488. PMID:31701655.
[16]
Corbin DR, Rehg JE, Shepherd DL, et al. Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2[J]. Mol Genet Metab, 2017, 120(4):350-362. DOI:10.1016/j.ymgme.2017.02.001. PMID:28189602.
[17]
Khatri D, Zizioli D, Trivedi A, et al. Overexpression of human mutant PANK2 proteins affects development and motor behavior of zebrafish embryos[J]. Neuromolecular Med, 2019, 21(2):120-131. DOI:10.1007/s12017-018-8508-8. PMID:30141000.
[18]
Arber C, Angelova PR, Wiethoff S, et al. iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease[J]. PLoS One, 2017, 12(9):e0184104. DOI:10.1371/journal.pone.0184104. PMID:28863176.
[19]
Guo YP, Tang BS, Guo JF. PLA2G6-associated neurodegeneration (PLAN):review of clinical phenotypes and genotypes[J]. Front Neurol, 2018, 9:1100. DOI:10.3389/fneur.2018.01100. PMID:30619057.
[20]
Malley KR, Koroleva O, Miller I, et al. The structure of iPLA2β reveals dimeric active sites and suggests mechanisms of regulation and localization[J]. Nat Commun, 2018, 9(1):765. DOI:10.1038/s41467-018-03193-0. PMID:29472584.
[21]
Lin G, Lee PT, Chen KC, et al. Phospholipase PLA2G6, a parkinsonism-associated gene, affects Vps26 and Vps35, retromer function, and ceramide levels, similar to α-synuclein gain[J]. Cell Metab, 2018, 28(4):605-618.e6. DOI:10.1016/j.cmet.2018.05.019. PMID:29909971.
[22]
Darling A, Aguilera-Albesa S, Tello CA, et al. PLA2G6-associated neurodegeneration:new insights into brain abnormalities and disease progression[J]. Parkinsonism Relat Disord, 2019, 61:179-186. DOI:10.1016/j.parkreldis.2018.10.013. PMID:30340910.
[23]
Hogarth P. Neurodegeneration with brain iron accumulation:diagnosis and management[J]. J Mov Disord, 2015, 8(1):1-13. DOI:10.14802/jmd.14034. PMID:25614780.
[24]
Koh K, Ichinose Y, Ishiura H, et al. PLA2G6-associated neurodegeneration presenting as a complicated form of hereditary spastic paraplegia[J]. J Hum Genet, 2019, 64(1):55-59. DOI:10.1038/s10038-018-0519-7. PMID:30302010.
Gitiaux C, Kaminska A, Boddaert N, et al. PLA2G6-associated neurodegeneration:lessons from neurophysiological findings[J]. Eur J Paediatr Neurol, 2018, 22(5):854-861. DOI:10.1016/j.ejpn.2018.05.005. PMID:29859652.
[27]
Rickman OJ, Salter CG, Gunning AC, et al. Dominant mitochondrial membrane protein-associated neurodegeneration (MPAN) variants cluster within a specific C19orf12 isoform[J]. Parkinsonism Relat Disord, 2021, 82:84-86. DOI:10.1016/j.parkreldis.2020.10.041. PMID:33260061.
[28]
Venco P, Bonora M, Giorgi C, et al. Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+[J]. Front Genet, 2015, 6:185. DOI:10.3389/fgene.2015.00185. PMID:26136767.
[29]
Hogarth P, Gregory A, Kruer MC, et al. New NBIA subtype:genetic, clinical, pathologic, and radiographic features of MPAN[J]. Neurology, 2013, 80(3):268-275. DOI:10.1212/WNL.0b013e31827e07be. PMID:23269600.
[30]
Dusek P, Mekle R, Skowronska M, et al. Brain iron and metabolic abnormalities in C19orf12 mutation carriers:a 7.0 tesla MRI study in mitochondrial membrane protein-associated neurodegeneration[J]. Mov Disord, 2020, 35(1):142-150. DOI:10.1002/mds.27827. PMID:31518459.
[31]
Wan HD, Wang Q, Chen XT, et al. WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death[J]. Autophagy, 2020, 16(3):531-547. DOI:10.1080/15548627.2019.1630224. PMID:31204559.
[32]
Hayflick SJ, Kruer MC, Gregory A, et al. β-Propeller protein-associated neurodegeneration:a new X-linked dominant disorder with brain iron accumulation[J]. Brain, 2013, 136(Pt 6):1708-1717. DOI:10.1093/brain/awt095. PMID:23687123.
[33]
DeBosch BJ, Heitmeier MR, Mayer AL, et al. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis[J]. Sci Signal, 2016, 9(416):ra21. DOI:10.1126/scisignal.aac5472. PMID:26905426.
[34]
Seibler P, Burbulla LF, Dulovic M, et al. Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells[J]. Brain, 2018, 141(10):3052-3064. DOI:10.1093/brain/awy230. PMID:30169597.
[35]
Aoun M, Tiranti V. Mitochondria:a crossroads for lipid metabolism defect in neurodegeneration with brain iron accumulation diseases[J]. Int J Biochem Cell Biol, 2015, 63:25-31. DOI:10.1016/j.biocel.2015.01.018. PMID:25668476.
[36]
Khatri D, Zizioli D, Tiso N, et al. Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish[J]. Sci Rep, 2016, 6:37660. DOI:10.1038/srep37660. PMID:27892483.
[37]
Drecourt A, Babdor J, Dussiot M, et al. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation[J]. Am J Hum Genet, 2018, 102(2):266-277. DOI:10.1016/j.ajhg.2018.01.003. PMID:29395073.
[38]
De Pace R, Skirzewski M, Damme M, et al. Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome[J]. PLoS Genet, 2018, 14(4):e1007363. DOI:10.1371/journal.pgen.1007363. PMID:29698489.
[39]
Zinoviev A, Goyal A, Jindal S, et al. Functions of unconventional mammalian translational GTPases GTPBP1 and GTPBP2[J]. Genes Dev, 2018, 32(17-18):1226-1241. DOI:10.1101/gad.314724.118. PMID:30108131.
[40]
Gillis WQ, Kirmizitas A, Iwasaki Y, et al. Gtpbp2 is a positive regulator of Wnt signaling and maintains low levels of the Wnt negative regulator Axin[J]. Cell Commun Signal, 2016, 14(1):15. DOI:10.1186/s12964-016-0138-x. PMID:27484226.
