Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect

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LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD.

Vyšlo v časopise: Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect. PLoS Genet 6(4): e32767. doi:10.1371/journal.pgen.1000914
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000914

Souhrn

Zdroje

1. ThomasB

BealMF

2007 Parkinson's disease. Hum Mol Genet 16 Spec No. 2 R183 194

2. DouglasMR

LewthwaiteAJ

NichollDJ

2007 Genetics of Parkinson's disease and parkinsonism. Expert Rev Neurother 7 657 666

3. SchapiraAH

2006 Etiology of Parkinson's disease. Neurology 66 S10 23

4. Paisan-RuizC

JainS

EvansEW

GilksWP

SimonJ

2004 Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44 595 600

5. RossOA

2007 Lrrking in the background: common pathways of neurodegeneration. J Am Geriatr Soc 55 804 805

6. ZimprichA

BiskupS

LeitnerP

LichtnerP

FarrerM

2004 Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44 601 607

7. FungHC

ChenCM

HardyJ

HernandezD

SingletonA

2006 Lack of G2019S LRRK2 mutation in a cohort of Taiwanese with sporadic Parkinson's disease. Mov Disord 21 880 881

8. OzeliusLJ

SenthilG

Saunders-PullmanR

OhmannE

DeligtischA

2006 LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med 354 424 425

9. SchapiraAH

2006 The importance of LRRK2 mutations in Parkinson disease. Arch Neurol 63 1225 1228

10. Di FonzoA

Wu-ChouYH

LuCS

van DoeselaarM

SimonsEJ

2006 A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 7 133 138

11. TanEK

2006 Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease. Ann Acad Med Singapore 35 840 842

12. GandhiPN

WangX

ZhuX

ChenSG

Wilson-DelfosseAL

2008 The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res 86 1711 1720

13. LesageS

DurrA

BriceA

2007 LRRK2: a link between familial and sporadic Parkinson's disease? Pathol Biol (Paris) 55 107 110

14. MarinI

2006 The Parkinson disease gene LRRK2: evolutionary and structural insights. Mol Biol Evol 23 2423 2433

15. MataIF

WedemeyerWJ

FarrerMJ

TaylorJP

GalloKA

2006 LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 29 286 293

16. GandhiPN

ChenSG

Wilson-DelfosseAL

2009 Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease. J Neurosci Res 87 1283 1295

17. MacLeodD

DowmanJ

HammondR

LeeteT

InoueK

2006 The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52 587 593

18. JaleelM

NicholsRJ

DeakM

CampbellDG

GillardonF

2007 LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. Biochem J 405 307 317

19. WangD

TangB

ZhaoG

PanQ

XiaK

2008 Dispensable role of Drosophila ortholog of LRRK2 kinase activity in survival of dopaminergic neurons. Mol Neurodegener 3 3

20. LeeSB

KimW

LeeS

ChungJ

2007 Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem Biophys Res Commun 358 534 539

21. TanEK

2007 The role of common genetic risk variants in Parkinson disease. Clin Genet 72 387 393

22. ScheerN

GrothA

HansS

Campos-OrtegaJA

2001 An instructive function for Notch in promoting gliogenesis in the zebrafish retina. Development 128 1099 1107

23. HigashiS

BiskupS

WestAB

TrinkausD

DawsonVL

2007 Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Res 1155 208 219

24. TaymansJM

Van den HauteC

BaekelandtV

2006 Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem 98 951 961

25. LiX

TanYC

PouloseS

OlanowCW

HuangXY

2007 Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem 103 238 247

26. Thierry-MiegD

Thierry-MiegJ

2006 AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 7 Suppl 1 S12 11 14

27. WangL

XieC

GreggioE

ParisiadouL

ShimH

2008 The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2. J Neurosci 28 3384 3391

28. GreggioE

ZambranoI

KaganovichA

BeilinaA

TaymansJM

2008 The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 283 16906 16914

29. MelroseH

2008 Update on the functional biology of Lrrk2. Future Neurol 3 669 681

30. FarrerMJ

HulihanMM

KachergusJM

DachselJC

StoesslAJ

2009 DCTN1 mutations in Perry syndrome. Nat Genet 41 163 165

31. LiD

RobertsR

2001 WD-repeat proteins: structure characteristics, biological function, and their involvement in human diseases. Cell Mol Life Sci 58 2085 2097

32. IaccarinoC

CrosioC

VitaleC

SannaG

CarriMT

2007 Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 16 1319 1326

33. TanEK

ZhaoY

SkipperL

TanMG

Di FonzoA

2007 The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Hum Genet 120 857 863

34. NagatsuaT

SawadabM

2009 L-dopa therapy for Parkinson's disease: past, present, and future. Parkinsonism Relat Disord 15 Suppl 1 S3 8

35. BretaudS

LeeS

GuoS

2004 Sensitivity of zebrafish to environmental toxins implicated in Parkinson's disease. Neurotoxicol Teratol 26 857 864

36. LamCS

KorzhV

StrahleU

2005 Zebrafish embryos are susceptible to the dopaminergic neurotoxin MPTP. Eur J Neurosci 21 1758 1762

37. ChenL

CagniardB

MathewsT

JonesS

KohHC

2005 Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J Biol Chem 280 21418 21426

38. GoldbergMS

PisaniA

HaburcakM

VorthermsTA

KitadaT

2005 Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron 45 489 496

39. KimRH

SmithPD

AleyasinH

HayleyS

MountMP

2005 Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci U S A 102 5215 5220

40. BretaudS

AllenC

InghamPW

BandmannO

2007 p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. J Neurochem 100 1626 1635

41. ZhouH

FalkenburgerBH

SchulzJB

TieuK

XuZ

2007 Silencing of the Pink1 gene expression by conditional RNAi does not induce dopaminergic neuron death in mice. Int J Biol Sci 3 242 250

42. KitadaT

PisaniA

PorterDR

YamaguchiH

TscherterA

2007 Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A 104 11441 11446

43. GoldbergMS

FlemingSM

PalacinoJJ

CepedaC

LamHA

2003 Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem 278 43628 43635

44. SonOL

KimHT

JiMH

YooKW

RheeM

2003 Cloning and expression analysis of a Parkinson's disease gene, uch-L1, and its promoter in zebrafish. Biochem Biophys Res Commun 312 601 607

45. FeanyMB

BenderWW

2000 A Drosophila model of Parkinson's disease. Nature 404 394 398

46. HaywoodAF

StaveleyBE

2004 Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci 5 14

47. PesahY

PhamT

BurgessH

MiddlebrooksB

VerstrekenP

2004 Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131 2183 2194

48. ChaGH

KimS

ParkJ

LeeE

KimM

2005 Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc Natl Acad Sci U S A 102 10345 10350

49. WhitworthAJ

TheodoreDA

GreeneJC

BenesH

WesPD

2005 Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc Natl Acad Sci U S A 102 8024 8029

50. LiuZ

WangX

YuY

LiX

WangT

2008 A Drosophila model for LRRK2-linked parkinsonism. Proc Natl Acad Sci U S A 105 2693 2698

51. MarinI

2008 Ancient origin of the Parkinson disease gene LRRK2. J Mol Evol 67 41 50

52. HendricksM

JesuthasanS

2007 Electroporation-based methods for in vivo, whole mount and primary culture analysis of zebrafish brain development. Neural Dev 2 6