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Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways

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Abstract

This study aimed to gain insights into the pathophysiology underlying PLA2G6-associated neurodegeneration that is implicated in three different neurological disorders, suggesting that other, unknown genetic or environmental factors might contribute to its wide phenotypic expression. To accomplish this, we downregulated the function of pla2g6 in the zebrafish nervous system, performed parkinsonism-related phenotypic characterization, and determined the effects of gene regulation upon the loss of pla2g6 function by using RNA sequencing and downstream analyses. Pla2g6 deficiency resulted in axonal degeneration, dopaminergic and motor neuron cell loss, and increased β-synuclein expression. We also observed that many of the identified, differentially expressed genes were implicated in other brain disorders, which might explain the variable phenotypic expression of pla2g6-associated disease, and found that top enriched canonical pathways included those already known or suggested to play a major role in the pathogenesis of Parkinson’s disease. Our data support that pla2g6 is relevant for cranial motor development with significant implications in the pathophysiology underlying Parkinson’s disease.

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References

  1. Gallati S (2014) Disease-modifying genes and monogenic disorders: experience in cystic fibrosis. Appl Clin Genet 7:133–146. https://doi.org/10.2147/TACG.S18675

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Gropman AL, Adams DR (2007) Atypical patterns of inheritance. Semin Pediatr Neurol 14(1):34–45. https://doi.org/10.1016/j.spen.2006.11.007

    Article  PubMed  Google Scholar 

  3. Krebs CE, Paisan-Ruiz C (2012) The use of next-generation sequencing in movement disorders. Front Genet 3:75

    Article  PubMed  PubMed Central  Google Scholar 

  4. Khateeb S, Flusser H, Ofir R, Shelef I, Narkis G, Vardi G, Shorer Z, Levy R et al (2006) PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet 79(5):942–948. https://doi.org/10.1086/508572

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J et al (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 38(7):752–754. https://doi.org/10.1038/ng1826

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Paisan-Ruiz C, Bhatia KP, Li A, Hernandez D, Davis M, Wood NW, Hardy J, Houlden H et al (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 65(1):19–23. https://doi.org/10.1002/ana.21415

    Article  PubMed  Google Scholar 

  7. Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G (2011) Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev 111(10):6130–6185. https://doi.org/10.1021/cr200085w

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Turk J, Ramanadham S (2004) The expression and function of a group VIA calcium-independent phospholipase A2 (iPLA2beta) in beta-cells. Can J Physiol Pharmacol 82(10):824–832. https://doi.org/10.1139/y04-064

    Article  PubMed  CAS  Google Scholar 

  9. Gregory A, Hayflick S (1993) Neurodegeneration with brain iron accumulation disorders overview. In: Pagon RA, Adam MP, Ardinger HH et al. (eds) GeneReviews(R). University of Washington, Seattle

    Google Scholar 

  10. Paisan-Ruiz C, Guevara R, Federoff M, Hanagasi H, Sina F, Elahi E, Schneider SA, Schwingenschuh P et al (2010) Early-onset L-dopa-responsive parkinsonism with pyramidal signs due to ATP13A2, PLA2G6, FBXO7 and spatacsin mutations. Mov Disord 25(12):1791–1800. https://doi.org/10.1002/mds.23221

    Article  PubMed  PubMed Central  Google Scholar 

  11. Budick SA, O’Malley DM (2000) Locomotor repertoire of the larval zebrafish: swimming, turning and prey capture. J Exp Biol 203(Pt 17):2565–2579

    PubMed  CAS  Google Scholar 

  12. Kastenhuber E, Kratochwil CF, Ryu S, Schweitzer J, Driever W (2010) Genetic dissection of dopaminergic and noradrenergic contributions to catecholaminergic tracts in early larval zebrafish. J Comp Neurol 518(4):439–458. https://doi.org/10.1002/cne.22214

    Article  PubMed  CAS  Google Scholar 

  13. Yamamoto K, Ruuskanen JO, Wullimann MF, Vernier P (2010) Two tyrosine hydroxylase genes in vertebrates. New dopaminergic territories revealed in the zebrafish brain. Mol Cell Neurosci 43(4):394–402. https://doi.org/10.1016/j.mcn.2010.01.006

    Article  PubMed  CAS  Google Scholar 

  14. Schweitzer J, Lohr H, Filippi A, Driever W (2012) Dopaminergic and noradrenergic circuit development in zebrafish. Dev Neurobiol 72(3):256–268. https://doi.org/10.1002/dneu.20911

    Article  PubMed  CAS  Google Scholar 

  15. Kaslin J, Panula P (2001) Comparative anatomy of the histaminergic and other aminergic systems in zebrafish (Danio rerio). J Comp Neurol 440(4):342–377. https://doi.org/10.1002/cne.1390

    Article  PubMed  CAS  Google Scholar 

  16. Bandmann O, Burton EA (2010) Genetic zebrafish models of neurodegenerative diseases. Neurobiol Dis 40(1):58–65. https://doi.org/10.1016/j.nbd.2010.05.017

    Article  PubMed  CAS  Google Scholar 

  17. Martin-Jimenez R, Campanella M, Russell C (2015) New zebrafish models of neurodegeneration. Curr Neurol Neurosci Rep 15(6):33

    Article  PubMed  CAS  Google Scholar 

  18. Xi Y, Noble S, Ekker M (2011) Modeling neurodegeneration in zebrafish. Curr Neurol Neurosci Rep 11(3):274–282. https://doi.org/10.1007/s11910-011-0182-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Xi Y, Ryan J, Noble S, Yu M, Yilbas AE, Ekker M (2010) Impaired dopaminergic neuron development and locomotor function in zebrafish with loss of pink1 function. Eur J Neurosci 31(4):623–633. https://doi.org/10.1111/j.1460-9568.2010.07091.x

    Article  PubMed  Google Scholar 

  20. Flinn L, Mortiboys H, Volkmann K, Koster RW, Ingham PW, Bandmann O (2009) Complex I deficiency and dopaminergic neuronal cell loss in parkin-deficient zebrafish (Danio rerio). Brain 132(Pt 6):1613–1623. https://doi.org/10.1093/brain/awp108

    Article  PubMed  Google Scholar 

  21. Sheng D, Qu D, Kwok KH, Ng SS, Lim AY, Aw SS, Lee CW, Sung WK et al (2010) Deletion of the WD40 domain of LRRK2 in zebrafish causes parkinsonism-like loss of neurons and locomotive defect. PLoS Genet 6(4):e1000914. https://doi.org/10.1371/journal.pgen.1000914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  PubMed  CAS  Google Scholar 

  23. Thisse C, Thisse B (2008) High-resolution in situ hybridization to whole-mount zebrafish embryos. Nat Protoc 3(1):59–69. https://doi.org/10.1038/nprot.2007.514

    Article  PubMed  CAS  Google Scholar 

  24. Turner KJ, Bracewell TG, Hawkins TA (2014) Anatomical dissection of zebrafish brain development. Methods Mol Biol 1082:197–214. https://doi.org/10.1007/978-1-62703-655-9_14

    Article  PubMed  Google Scholar 

  25. Trapnell C, Pachter L, Salzberg SL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25(9):1105–1111. https://doi.org/10.1093/bioinformatics/btp120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Roberts A, Pimentel H, Trapnell C, Pachter L (2011) Identification of novel transcripts in annotated genomes using RNA-Seq. Bioinformatics 27(17):2325–2329. https://doi.org/10.1093/bioinformatics/btr355

    Article  PubMed  CAS  Google Scholar 

  27. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z (2009) GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10(1):48. https://doi.org/10.1186/1471-2105-10-48

    Article  PubMed  PubMed Central  Google Scholar 

  28. Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S, Kong L, Gao G et al (2011) KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res 39(Web Server issue):W316–W322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Sina F, Shojaee S, Elahi E, Paisan-Ruiz C (2009) R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family. Eur J Neurol 16(1):101–104. https://doi.org/10.1111/j.1468-1331.2008.02356.x

    Article  PubMed  CAS  Google Scholar 

  30. Filippi A, Mahler J, Schweitzer J, Driever W (2010) Expression of the paralogous tyrosine hydroxylase encoding genes th1 and th2 reveals the full complement of dopaminergic and noradrenergic neurons in zebrafish larval and juvenile brain. J Comp Neurol 518(4):423–438. https://doi.org/10.1002/cne.22213

    Article  PubMed  CAS  Google Scholar 

  31. George JM (2002) The synucleins. Genome Biol 3(1):REVIEWS3002

    PubMed  Google Scholar 

  32. Lee VM, Trojanowski JQ (2006) Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 52(1):33–38. https://doi.org/10.1016/j.neuron.2006.09.026

    Article  PubMed  CAS  Google Scholar 

  33. Stefanis L (2012) Alpha-synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med 2(2):a009399

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Paisan-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R, Kidd D, Chataway J, Bhatia KP et al (2010) Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 33(4):814–823. https://doi.org/10.1016/j.neurobiolaging.2010.05.009

    Article  PubMed  CAS  Google Scholar 

  35. Scherzer CR, Jensen RV, Gullans SR, Feany MB (2003) Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease. Hum Mol Genet 12(19):2457–2466. https://doi.org/10.1093/hmg/ddg265

    Article  PubMed  CAS  Google Scholar 

  36. Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, Wozniak DF, Schmidt RE, Gross RW et al (2008) Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol 172(2):406–416. https://doi.org/10.2353/ajpath.2008.070823

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sun Z, Gitler AD (2008) Discovery and characterization of three novel synuclein genes in zebrafish. Dev Dyn 237(9):2490–2495. https://doi.org/10.1002/dvdy.21569

    Article  PubMed  CAS  Google Scholar 

  38. Zannino DA, Appel B (2009) Olig2+ precursors produce abducens motor neurons and oligodendrocytes in the zebrafish hindbrain. J Neurosci 29(8):2322–2333. https://doi.org/10.1523/JNEUROSCI.3755-08.2009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Devine CA, Key B (2003) Identifying axon guidance defects in the embryonic zebrafish brain. Methods Cell Sci 25(1–2):33–37. https://doi.org/10.1023/B:MICS.0000006851.84998.e0

    Article  PubMed  CAS  Google Scholar 

  40. Uryu K, Richter-Landsberg C, Welch W, Sun E, Goldbaum O, Norris EH, Pham CT, Yazawa I et al (2006) Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies. Am J Pathol 168(3):947–961. https://doi.org/10.2353/ajpath.2006.050770

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Jeon GS, Park SW, Kim DW, Seo JH, Cho J, Lim SY, Kim SD, Cho SS (2004) Glial expression of the 90-kDa heat shock protein (HSP90) and the 94-kDa glucose-regulated protein (GRP94) following an excitotoxic lesion in the mouse hippocampus. Glia 48(3):250–258. https://doi.org/10.1002/glia.20075

    Article  PubMed  Google Scholar 

  42. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19(24):4861–4870. https://doi.org/10.1093/hmg/ddq419

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. de Carvalho AP, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M et al (2004) Mutations in the Na+/K+-ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 43(2):169–175. https://doi.org/10.1016/j.neuron.2004.06.028

    Article  Google Scholar 

  44. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA et al (1997) Niemann-pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277(5323):228–231. https://doi.org/10.1126/science.277.5323.228

    Article  PubMed  CAS  Google Scholar 

  45. Weber YG, Storch A, Wuttke TV, Brockmann K, Kempfle J, Maljevic S, Margari L, Kamm C et al (2008) GLUT1 mutations are a cause of paroxysmal exertion-induced dyskinesias and induce hemolytic anemia by a cation leak. J Clin Invest 118(6):2157–2168. https://doi.org/10.1172/JCI34438

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Weber YG, Kamm C, Suls A, Kempfle J, Kotschet K, Schule R, Wuttke TV, Maljevic S et al (2011) Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 77(10):959–964. https://doi.org/10.1212/WNL.0b013e31822e0479

    Article  PubMed  CAS  Google Scholar 

  47. Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C, Parrini E, Valence S, Pierre BS, Oger M, Lacombe D, Genevieve D, Fontana E, Darra F, Cances C, Barth M, Bonneau D, Bernadina BD, N’Guyen S, Gitiaux C, Parent P, des Portes V, Pedespan JM, Legrez V, Castelnau-Ptakine L, Nitschke P, Hieu T, Masson C, Zelenika D, Andrieux A, Francis F, Guerrini R, Cowan NJ, Bahi-Buisson N, Chelly J (2013) Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet 45 (6):639–647, doi: https://doi.org/10.1038/ng.2613.

  48. Rauch SM, Huen K, Miller MC, Chaudry H, Lau M, Sanes JR, Johanson CE, Stopa EG et al (2011) Changes in brain beta-amyloid deposition and aquaporin 4 levels in response to altered agrin expression in mice. J Neuropathol Exp Neurol 70(12):1124–1137. https://doi.org/10.1097/NEN.0b013e31823b0b12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Garthwaite J, Boulton CL (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57(1):683–706. https://doi.org/10.1146/annurev.ph.57.030195.003343

    Article  PubMed  CAS  Google Scholar 

  50. Falls DL (2003) Neuregulins: Functions, forms, and signaling strategies. Exp Cell Res 284(1):14–30. https://doi.org/10.1016/S0014-4827(02)00102-7

    Article  PubMed  CAS  Google Scholar 

  51. Wu GY, Deisseroth K, Tsien RW (2001) Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A 98(5):2808–2813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Knapp RJ, Malatynska E, Yamamura HI (1990) From binding studies to the molecular biology of GABA receptors. Neurochem Res 15(2):105–112. https://doi.org/10.1007/BF00972199

    Article  PubMed  CAS  Google Scholar 

  53. Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci 18(2):101–113. https://doi.org/10.1038/nrn.2016.178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Zhao T, Zondervan-van der Linde H, Severijnen LA, Oostra BA, Willemsen R, Bonifati V (2012) Dopaminergic neuronal loss and dopamine-dependent locomotor defects in Fbxo7-deficient zebrafish. PLoS One 7(11):e48911. https://doi.org/10.1371/journal.pone.0048911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Anichtchik O, Diekmann H, Fleming A, Roach A, Goldsmith P, Rubinsztein DC (2008) Loss of PINK1 function affects development and results in neurodegeneration in zebrafish. J Neurosci 28(33):8199–8207. https://doi.org/10.1523/JNEUROSCI.0979-08.2008

    Article  PubMed  CAS  Google Scholar 

  56. Sallinen V, Kolehmainen J, Priyadarshini M, Toleikyte G, Chen YC, Panula P (2010) Dopaminergic cell damage and vulnerability to MPTP in Pink1 knockdown zebrafish. Neurobiol Dis 40(1):93–101. https://doi.org/10.1016/j.nbd.2010.06.001

    Article  PubMed  CAS  Google Scholar 

  57. Wilson JM, Levey AI, Rajput A, Ang L, Guttman M, Shannak K, Niznik HB, Hornykiewicz O et al (1996) Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson’s disease. Neurology 47(3):718–726. https://doi.org/10.1212/WNL.47.3.718

    Article  PubMed  CAS  Google Scholar 

  58. Schulz-Schaeffer WJ (2010) The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 120(2):131–143. https://doi.org/10.1007/s00401-010-0711-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Abeliovich A, Gitler AD (2016) Defects in trafficking bridge Parkinson’s disease pathology and genetics. Nature 539(7628):207–216. https://doi.org/10.1038/nature20414

    Article  PubMed  Google Scholar 

  60. Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF, Wokosin D, Ilijic E et al (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9(2):251–259. https://doi.org/10.1038/nn1632

    Article  PubMed  CAS  Google Scholar 

  61. Sumi-Akamaru H, Beck G, Shinzawa K, Kato S, Riku Y, Yoshida M, Fujimura H, Tsujimoto Y et al (2016) High expression of alpha-synuclein in damaged mitochondria with PLA2G6 dysfunction. Acta Neuropathol Commun 4(1):27. https://doi.org/10.1186/s40478-016-0298-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Hikosaka O, Sesack SR, Lecourtier L, Shepard PD (2008) Habenula: crossroad between the basal ganglia and the limbic system. J Neurosci 28(46):11825–11829. https://doi.org/10.1523/JNEUROSCI.3463-08.2008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Illingworth MA, Meyer E, Chong WK, Manzur AY, Carr LJ, Younis R, Hardy C, McDonald F et al (2014) PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab 112(2):183–189. https://doi.org/10.1016/j.ymgme.2014.03.008

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sumi-Akamaru H, Beck G, Kato S, Mochizuki H (2015) Neuroaxonal dystrophy in PLA2G6 knockout mice. Neuropathology 35(3):289–302. https://doi.org/10.1111/neup.12202

    Article  PubMed  CAS  Google Scholar 

  65. Labrador-Garrido A, Bertoncini CW, Roodveldt C (2011) The Hsp70 chaperone system in Parkinson’s disease, etiology and pathophysiology of Parkinson’s disease. In: PAQR (ed). InTech.

  66. Daturpalli S, Waudby CA, Meehan S, Jackson SE (2013) Hsp90 inhibits alpha-synuclein aggregation by interacting with soluble oligomers. J Mol Biol 425(22):4614–4628. https://doi.org/10.1016/j.jmb.2013.08.006

    Article  PubMed  CAS  Google Scholar 

  67. Ebrahimi-Fakhari D, Saidi LJ, Wahlster L (2013) Molecular chaperones and protein folding as therapeutic targets in Parkinson’s disease and other synucleinopathies. Acta Neuropathol Commun 1(1):79. https://doi.org/10.1186/2051-5960-1-79

    Article  PubMed  PubMed Central  Google Scholar 

  68. Minoia M, Grit C, Kampinga HH (2014) HSPA1A-independent suppression of PARK2 C289G protein aggregation by human small heat shock proteins. Mol Cell Biol 34(19):3570–3578. https://doi.org/10.1128/MCB.00698-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N et al (2004) Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet 36(6):602–606. https://doi.org/10.1038/ng1354

    Article  PubMed  CAS  Google Scholar 

  70. Abisambra JF, Jinwal UK, Jones JR, Blair LJ, Koren J 3rd, Dickey CA (2011) Exploiting the diversity of the heat-shock protein family for primary and secondary tauopathy therapeutics. Curr Neuropharmacol 9(4):623–631. https://doi.org/10.2174/157015911798376226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Zuchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E et al (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36(5):449–451. https://doi.org/10.1038/ng1341

    Article  PubMed  CAS  Google Scholar 

  72. Fyfe JC, Al-Tamimi RA, Liu J, Schaffer AA, Agarwala R, Henthorn PS (2011) A novel mitofusin 2 mutation causes canine fetal-onset neuroaxonal dystrophy. Neurogenetics 12(3):223–232. https://doi.org/10.1007/s10048-011-0285-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114(Pt 5):867–874

    PubMed  CAS  Google Scholar 

  74. Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340(6131):471–475. https://doi.org/10.1126/science.1231031

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ, Pallanck LJ (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci U S A 105(5):1638–1643. https://doi.org/10.1073/pnas.0709336105

    Article  PubMed  PubMed Central  Google Scholar 

  76. Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, Yoo SJ, Hay BA et al (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441(7097):1162–1166. https://doi.org/10.1038/nature04779

    Article  PubMed  CAS  Google Scholar 

  77. Lee S, Sterky FH, Mourier A, Terzioglu M, Cullheim S, Olson L, Larsson NG (2012) Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons. Hum Mol Genet 21(22):4827–4835. https://doi.org/10.1093/hmg/dds352

    Article  PubMed  CAS  Google Scholar 

  78. Kreitzer AC, Malenka RC (2008) Striatal plasticity and basal ganglia circuit function. Neuron 60(4):543–554. https://doi.org/10.1016/j.neuron.2008.11.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank Joshua Barber at the Zebrafish core at the Columbia University Medical Center for his assistance with the MO and mRNA microinjections and the staff at the Microscopy Shared Resource Facility at the ISMMS for their training and assistance with the zebrafish imaging.

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS079388; CPR).

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Authors and Affiliations

  1. Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Elena Sánchez, Luis J. Azcona & Coro Paisán-Ruiz

  2. Department of Neurosciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Luis J. Azcona

  3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Coro Paisán-Ruiz

  4. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Coro Paisán-Ruiz

  5. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Coro Paisán-Ruiz

  6. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA

    Coro Paisán-Ruiz

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  1. Elena Sánchez
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Correspondence to Coro Paisán-Ruiz.

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All experiments involving animals were performed under the national (United States National Institutes of Health) and Institutional Animal Care and Use Committee at the Icahn School of Medicine at Mount Sinai (ISMMS) guidelines and approved by ISMMS IACUC (Protocol number: LA11-00313).

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Sánchez, E., Azcona, L.J. & Paisán-Ruiz, C. Pla2g6 Deficiency in Zebrafish Leads to Dopaminergic Cell Death, Axonal Degeneration, Increased β-Synuclein Expression, and Defects in Brain Functions and Pathways. Mol Neurobiol 55, 6734–6754 (2018). https://doi.org/10.1007/s12035-017-0846-2

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  • DOI: https://doi.org/10.1007/s12035-017-0846-2

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