The locomotor deficits associated with Parkinson disease result from the death of a specific subset of dopamine neurons in the ventral part of the midbrain. The reason for the greater sensitivity to degeneration of those, relative to other, neurons is not clear. Prior work showed that the Pitx3 transcription factor is specifically expressed in these neurons where it has a survival role during development. The present work identified a cell signaling component, Rgs6, that is also restricted to the sensitive neurons in the midbrain and that exerts a protective function, particularly late in life. While the loss of Rgs6 function may predispose or contribute to Parkinson disease, its stimulation may provide a novel therapeutic avenue to treat Parkinson disease.
Vyšlo v časopise: is Required for Adult Maintenance of Dopaminergic Neurons in the Ventral Substantia Nigra. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004863 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004863
1. JellingerKA (2012) Neuropathology of sporadic Parkinson's disease: evaluation and changes of concepts. Mov Disord 27 : 8–30.
2. Gonzalez-HernandezT, Cruz-MurosI, Afonso-OramasD, Salas-HernandezJ, Castro-HernandezJ (2010) Vulnerability of mesostriatal dopaminergic neurons in Parkinson's disease. Front Neuroanat 4 : 140.
3. ObesoJA, Rodriguez-OrozMC, GoetzCG, MarinC, KordowerJH, et al. (2010) Missing pieces in the Parkinson's disease puzzle. Nat Med 16 : 653–661.
4. DawsonTM, KoHS, DawsonVL (2010) Genetic animal models of Parkinson's disease. Neuron 66 : 646–661.
5. WesterlundM, HofferB, OlsonL (2010) Parkinson's disease: Exit toxins, enter genetics. Prog Neurobiol 90 : 146–156.
6. LiY, LiuW, OoTF, WangL, TangY, et al. (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat Neurosci 12 : 826–828.
7. RousseauxMW, MarcogliesePC, QuD, HewittSJ, SeangS, et al. (2012) Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proc Natl Acad Sci U S A 109 : 15918–15923.
8. DaveKD, De SilvaS, ShethNP, RambozS, BeckMJ, et al. (2014) Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease. Neurobiol Dis 70 : 190–203..
9. LissB, NeuA, RoeperJ (1999) The weaver mouse gain-of-function phenotype of dopaminergic midbrain neurons is determined by coactivation of wvGirk2 and K-ATP channels. J Neurosci 19 : 8839–8848.
10. SmitsSM, BurbachJP, SmidtMP (2006) Developmental origin and fate of meso-diencephalic dopamine neurons. Prog Neurobiol 78 : 1–16.
11. SimeoneA, Di SalvioM, Di GiovannantonioLG, AcamporaD, OmodeiD, TomasettiC (2011) The role of otx2 in adult mesencephalic-diencephalic dopaminergic neurons. Mol Neurobiol 43 : 107–113.
12. van den MunckhofP, LukKC, Sainte-MarieL, MontgomeryJ, BlanchetPJ, et al. (2003) Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 130 : 2535–2542.
13. HwangDY, ArdayfioP, KangUJ, SeminaEV, KimKS (2003) Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res Mol Brain Res 114 : 123–131.
14. NunesI, TovmasianLT, SilvaRM, BurkeRE, GoffSP (2003) Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci USA 100 : 4245–4250.
15. LukKC, RymarVV, van den MunckhofP, NicolauS, SteriadeC, et al. (2013) The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress. J Neurochem 125 : 932–943.
16. van den MunckhofP, GilbertF, ChamberlandM, LévesqueD, DrouinJ (2006) Striatal neuroadaptation and rescue of locomotor deficit by L-dopa in aphakia mice, a model of Parkinson's disease. J Neurochem 96 : 160–170.
17. HwangDY, FlemingSM, ArdayfioP, Moran-GatesT, KimH, et al. (2005) 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease. J Neurosci 25 : 2132–2137.
18. FuchsJ, MuellerJC, LichtnerP, SchulteC, MunzM, et al. (2007) The transcription factor PITX3 is associated with sporadic Parkinson's disease. Neurobiol Aging 30 : 731–8..
19. JacobsFM, VeenvlietJV, AlmirzaWH, HoekstraEJ, von OerthelL, et al. (2011) Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons. Development 138 : 5213–5222.
20. JacobsFM, SmitsSM, NoorlanderCW, von OerthelL, van der LindenAJ, et al. (2007) Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3 deficiency. Development 134 : 2673–2684.
21. LiuG, YuJ, DingJ, XieC, SunL, et al. (2014) Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. J Clin Invest 124 : 3032–3046.
22. JacobsFM, van ErpS, van der LindenAJ, von OerthelL, BurbachJP, et al. (2009) Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression. Development 136 : 531–540.
23. PengC, AronL, KleinR, LiM, WurstW, et al. (2011) Pitx3 is a critical mediator of GDNF-induced BDNF expression in nigrostriatal dopaminergic neurons. J Neurosci 31 : 12802–12815.
24. PascualA, Hidalgo-FigueroaM, PiruatJI, PintadoCO, Gomez-DiazR, et al. (2008) Absolute requirement of GDNF for adult catecholaminergic neuron survival. Nat Neurosci 11 : 755–761.
25. AndersonGR, PosokhovaE, MartemyanovKA (2009) The R7 RGS protein family: multi-subunit regulators of neuronal G protein signaling. Cell Biochem Biophys 54 : 33–46.
26. YangJ, HuangJ, MaityB, GaoZ, LorcaRA, et al. (2010) RGS6, a modulator of parasympathetic activation in heart. Circ Res 107 : 1345–1349.
27. PosokhovaE, WydevenN, AllenKL, WickmanK, MartemyanovKA (2010) RGS6/Gbeta5 complex accelerates IKACh gating kinetics in atrial myocytes and modulates parasympathetic regulation of heart rate. Circ Res 107 : 1350–1354.
28. MaityB, StewartA, YangJ, LooL, SheffD, et al. (2012) Regulator of G protein signaling 6 (RGS6) protein ensures coordination of motor movement by modulating GABAB receptor signaling. J Biol Chem 287 : 4972–4981.
29. StewartA, MaityB, WunschAM, MengF, WuQ, et al. (2014) Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis. FASEB J 28 : 1735–1744.
30. FuY, YuanY, HallidayG, RusznakZ, WatsonC, et al. (2012) A cytoarchitectonic and chemoarchitectonic analysis of the dopamine cell groups in the substantia nigra, ventral tegmental area, and retrorubral field in the mouse. Brain Struct Funct 217 : 591–612.
31. Di SalvioM, Di GiovannantonioLG, AcamporaD, ProsperiR, OmodeiD, et al. (2010) Otx2 controls neuron subtype identity in ventral tegmental area and antagonizes vulnerability to MPTP. Nat Neurosci 13 : 1481–1488.
32. MoellerC, YaylaogluMB, Alvarez-BoladoG, ThallerC, EicheleG (2002) Murine Lix1, a novel marker for substantia nigra, cortical layer 5, and hindbrain structures. Brain Res Gene Expr Patterns 1 : 199–203.
33. BianGL, WeiLC, ShiM, WangYQ, CaoR, et al. (2007) Fluoro-Jade C can specifically stain the degenerative neurons in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine-treated C57BL/6 mice. Brain Res 1150 : 55–61.
34. EharaA, UedaS (2009) Application of Fluoro-Jade C in acute and chronic neurodegeneration models: utilities and staining differences. Acta Histochem Cytochem 42 : 171–179.
35. Oliveras-SalvaM, Van RompuyAS, HeemanB, Van denHC, BaekelandtV (2011) Loss-of-function rodent models for parkin and PINK1. J Parkinsons Dis 1 : 229–251.
36. XieZ, ZhuangX, ChenL (2009) DJ-1 mRNA anatomical localization and cell type identification in the mouse brain. Neurosci Lett 465 : 214–219.
37. TaymansJM, Van denHC, BaekelandtV (2006) Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem 98 : 951–961.
38. OgawaO, LeeHG, ZhuX, RainaA, HarrisPL, et al. (2003) Increased p27, an essential component of cell cycle control, in Alzheimer's disease. Aging Cell 2 : 105–110.
39. MaityB, YangJ, HuangJ, AskelandRW, BeraS, et al. (2011) Regulator of G protein signaling 6 (RGS6) induces apoptosis via a mitochondrial-dependent pathway not involving its GTPase-activating protein activity. J Biol Chem 286 : 1409–1419.
40. LebelM, GauthierY, MoreauA, DrouinJ (2001) Pitx3 activates mouse tyrosine hydroxylase promoter via a high affinity binding site. J Neurochem 76 : 1–11.
41. BolanEA, KivellB, JaligamV, OzM, JayanthiLD, et al. (2007) D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism. Mol Pharmacol 71 : 1222–1232.
42. SondersMS, ZhuSJ, ZahniserNR, KavanaughMP, AmaraSG (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci 17 : 960–974.
43. VaughanRA, FosterJD (2013) Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci 34 : 489–496.
44. CaudleWM, RichardsonJR, WangMZ, TaylorTN, GuillotTS, et al. (2007) Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration. J Neurosci 27 : 8138–8148.
45. LipskiJ, NisticoR, BerrettaN, GuatteoE, BernardiG, et al. (2011) L-DOPA: a scapegoat for accelerated neurodegeneration in Parkinson's disease? Prog Neurobiol 94 : 389–407.
46. GrimmJ, MuellerA, HeftiF, RosenthalA (2004) Molecular basis for catecholaminergic neuron diversity. Proc Natl Acad Sci U S A 101 : 13891–13896.
47. GreeneJG, DingledineR, GreenamyreJT (2005) Gene expression profiling of rat midbrain dopamine neurons: implications for selective vulnerability in parkinsonism. Neurobiol Dis 18 : 19–31.
48. ChungCY, SeoH, SonntagKC, BrooksA, LinL, et al. (2005) Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet 14 : 1709–1725.
49. MelamedP, KohM, PreklathanP, BeiL, HewC (2002) Multiple mechanisms for Pitx-1 transactivation of a luteinizing hormone beta subunit gene. J Biol Chem 277 : 26200–26207.
50. Afonso-OramasD, Cruz-MurosI, AlvarezdlR, AbreuP, GiraldezT, et al. (2009) Dopamine transporter glycosylation correlates with the vulnerability of midbrain dopaminergic cells in Parkinson's disease. Neurobiol Dis 36 : 494–508.
51. SawamotoK, NakaoN, KobayashiK, MatsushitaN, TakahashiH, et al. (2001) Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons. Proc Natl Acad Sci USA 98 : 6423–6428.
52. L'HonoréA, CoulonV, MarcilA, LebelM, Lafrance-VanasseJ, et al. (2007) Sequential expression and redundancy of Pitx2 and Pitx3 genes during muscle development. Dev Biol 307 : 421–433.
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