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Open Access 01-12-2016 | Research

PINK1 expression increases during brain development and stem cell differentiation, and affects the development of GFAP-positive astrocytes

Authors: Insup Choi, Dong-Joo Choi, Haijie Yang, Joo Hong Woo, Mi-Yoon Chang, Joo Yeon Kim, Woong Sun, Sang-Myun Park, Ilo Jou, Sang-Hun Lee, Eun-Hye Joe

Published in: Molecular Brain | Issue 1/2016

Abstract

Background

Mutation of PTEN-induced putative kinase 1 (PINK1) causes autosomal recessive early-onset Parkinson’s disease (PD). Despite of its ubiquitous expression in brain, its roles in non-neuronal cells such as neural stem cells (NSCs) and astrocytes were poorly unknown.

Results

We show that PINK1 expression increases from embryonic day 12 to postnatal day 1 in mice, which represents the main period of brain development. PINK1 expression also increases during neural stem cell (NSC) differentiation. Interestingly, expression of GFAP (a marker of astrocytes) was lower in PINK1 knockout (KO) mouse brain lysates compared to wild-type (WT) lysates at postnatal days 1-8, whereas there was little difference in the expression of markers for other brain cell types (e.g., neurons and oligodendrocytes). Further experiments showed that PINK1-KO NSCs were defective in their differentiation to astrocytes, producing fewer GFAP-positive cells compared to WT NSCs. However, the KO and WT NSCs did not differ in their self-renewal capabilities or ability to differentiate to neurons and oligodendrocytes. Interestingly, during differentiation of KO NSCs there were no defects in mitochondrial function, and there were not changes in signaling molecules such as SMAD1/5/8, STAT3, and HES1 involved in differentiation of NSCs into astrocytes. In brain sections, GFAP-positive astrocytes were more sparsely distributed in the corpus callosum and substantia nigra of KO animals compared with WT.

Conclusion

Our study suggests that PINK1 deficiency causes defects in GFAP-positive astrogliogenesis during brain development and NSC differentiation, which may be a factor to increase risk for PD.

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Valente EM, Bentivoglio AR, Dixon PH, Ferraris A, Ialongo T, Frontali M, et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet. 2001;68(4):895–900.PubMedCentralCrossRefPubMed

Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science. 2004;304(5674):1158–60. doi:10.1126/science.1096284.CrossRefPubMed

Beilina A, Van Der Brug M, Ahmad R, Kesavapany S, Miller DW, Petsko GA, et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proc Natl Acad Sci U S A. 2005;102(16):5703–8. doi:10.1073/pnas.0500617102.PubMedCentralCrossRefPubMed

Liu W, Vives-Bauza C, Acin-Perez R, Yamamoto A, Tan Y, Li Y, et al. PINK1 defect causes mitochondrial dysfunction, proteasomal deficit and alpha-synuclein aggregation in cell culture models of Parkinson’s disease. PLoS ONE. 2009;4(2):e4597. doi:10.1371/journal.pone.0004597.PubMedCentralCrossRefPubMed

Sim CH, Lio DS, Mok SS, Masters CL, Hill AF, Culvenor JG, et al. C-terminal truncation and Parkinson’s disease-associated mutations down-regulate the protein serine/threonine kinase activity of PTEN-induced kinase-1. Hum Mol Genet. 2006;15(21):3251–62. doi:10.1093/hmg/ddl398.CrossRefPubMed

Gandhi S, Wood-Kaczmar A, Yao Z, Plun-Favreau H, Deas E, Klupsch K, et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell. 2009;33(5):627–38. doi:10.1016/j.molcel.2009.02.013.PubMedCentralCrossRefPubMed

Choi I, Kim J, Jeong HK, Kim B, Jou I, Park SM, et al. Pink1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced akt and increased p38 mapk activation, and downregulation of egfr. Glia. 2013;61(5):800–12. doi:10.1002/glia.22475.PubMedCentralCrossRefPubMed

Deng H, Jankovic J, Guo Y, Xie W, Le W. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochem Biophys Res Commun. 2005;337(4):1133–8. doi:10.1016/j.bbrc.2005.09.178.CrossRefPubMed

Haque ME, Thomas KJ, D’Souza C, Callaghan S, Kitada T, Slack RS, et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proc Natl Acad Sci U S A. 2008;105(5):1716–21. doi:10.1073/pnas.0705363105.PubMedCentralCrossRefPubMed

10.

Requejo-Aguilar R, Lopez-Fabuel I, Fernandez E, Martins LM, Almeida A, Bolanos JP. PINK1 deficiency sustains cell proliferation by reprogramming glucose metabolism through HIF1. Nat Commun. 2014;5:4514. doi:10.1038/ncomms5514.CrossRefPubMed

11.

Lin W, Wadlington NL, Chen L, Zhuang X, Brorson JR, Kang UJ. Loss of PINK1 attenuates HIF-1alpha induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia. J Neurosci. 2014;34(8):3079–89. doi:10.1523/JNEUROSCI.2286-13.2014.PubMedCentralCrossRefPubMed

12.

Kim J, Byun JW, Choi I, Kim B, Jeong HK, Jou I, et al. PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices. Exp Neurobiol. 2013;22(1):38–44. doi:10.5607/en.2013.22.1.38.PubMedCentralCrossRefPubMed

13.

Dagda RK, Pien I, Wang R, Zhu J, Wang KZ, Callio J, et al. Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through protein kinase A. J Neurochem. 2014;128(6):864–77. doi:10.1111/jnc.12494.PubMedCentralCrossRefPubMed

14.

Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science. 2001;291(5504):657–61. doi:10.1126/science.291.5504.657.CrossRefPubMed

15.

Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, et al. Control of synaptic strength by glial TNFalpha. Science. 2002;295(5563):2282–5. doi:10.1126/science.1067859.CrossRefPubMed

16.

Gage FH, Olejniczak P, Armstrong DM. Astrocytes are important for sprouting in the septohippocampal circuit. Exp Neurol. 1988;102(1):2–13.CrossRefPubMed

17.

Sakatani S, Seto-Ohshima A, Itohara S, Hirase H. Impact of S100B on local field potential patterns in anesthetized and kainic acid-induced seizure conditions in vivo. Eur J Neurosci. 2007;25(4):1144–54. doi:10.1111/j.1460-9568.2007.05337.x.CrossRefPubMed

18.

Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 2007;55(12):1263–71. doi:10.1002/glia.20557.CrossRefPubMed

19.

Chih CP, Roberts Jr EL. Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis. J Cereb Blood Flow Metab. 2003;23(11):1263–81. doi:10.1097/01.WCB.0000081369.51727.6F.CrossRefPubMed

20.

Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia. 2007;55(12):1251–62. doi:10.1002/glia.20528.CrossRefPubMed

21.

Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32(1):1–14.CrossRefPubMed

22.

Simard M, Nedergaard M. The neurobiology of glia in the context of water and ion homeostasis. Neuroscience. 2004;129(4):877–96. doi:10.1016/j.neuroscience.2004.09.053.CrossRefPubMed

23.

Wilson JX. Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol. 1997;75(10-11):1149–63.CrossRefPubMed

24.

Jeong HK, Jou I, Joe EH. Absence of Delayed Neuronal Death in ATP-Injected Brain: Possible Roles of Astrogliosis. Exp Neurobiol. 2013;22(4):308–14. doi:10.5607/en.2013.22.4.308.PubMedCentralCrossRefPubMed

25.

Jeong HK, Ji KM, Kim J, Jou I, Joe EH. Repair of astrocytes, blood vessels, and myelin in the injured brain: possible roles of blood monocytes. Mol Brain. 2013;6:28. doi:10.1186/1756-6606-6-28.PubMedCentralCrossRefPubMed

26.

Jeong HK, Ji KM, Min KJ, Choi I, Choi DJ, Jou I, et al. Astrogliosis is a possible player in preventing delayed neuronal death. Mol Cells. 2014;37(4):345–55. 10.14348/molcells.2014.0046.PubMedCentralCrossRefPubMed

27.

Kim JH, Min KJ, Seol W, Jou I, Joe EH. Astrocytes in injury states rapidly produce anti-inflammatory factors and attenuate microglial inflammatory responses. J Neurochem. 2010;115(5):1161–71. doi:10.1111/j.1471-4159.2010.07004.x.CrossRefPubMed

28.

Min KJ, Yang MS, Kim SU, Jou I, Joe EH. Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J Neurosci. 2006;26(6):1880–7. doi:10.1523/JNEUROSCI.3696-05.2006.CrossRefPubMed

29.

Gonzalez-Perez O, Quinones-Hinojosa A. Astrocytes as neural stem cells in the adult brain. J Stem Cells. 2012;7(3):181–8. jsc.2012.7.3.181.PubMedCentralPubMed

30.

Magnusson JP, Goritz C, Tatarishvili J, Dias DO, Smith EM, Lindvall O, et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science. 2014;346(6206):237–41. doi:10.1126/science.346.6206.237.CrossRefPubMed

31.

Armstrong RJ, Barker RA. Neurodegeneration: a failure of neuroregeneration? Lancet. 2001;358(9288):1174–6. doi:10.1016/S0140-6736(01)06260-2.CrossRefPubMed

32.

Miller FD, Gauthier AS. Timing is everything: making neurons versus glia in the developing cortex. Neuron. 2007;54(3):357–69. doi:10.1016/j.neuron.2007.04.019.CrossRefPubMed

33.

Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med. 2000;342(21):1560–7. doi:10.1056/NEJM200005253422103.CrossRefPubMed

34.

Xiong H, Wang D, Chen L, Choo YS, Ma H, Tang C, et al. Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. J Clin Invest. 2009;119(3):650–60. doi:10.1172/JCI37617.PubMedCentralCrossRefPubMed

35.

Rajan P, McKay RD. Multiple routes to astrocytic differentiation in the CNS. J Neurosci. 1998;18(10):3620–9.PubMed

36.

Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science. 1997;278(5337):477–83.CrossRefPubMed

37.

He F, Ge W, Martinowich K, Becker-Catania S, Coskun V, Zhu W, et al. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci. 2005;8(5):616–25. doi:10.1038/nn1440.PubMedCentralCrossRefPubMed

38.

Nakashima K, Yanagisawa M, Arakawa H, Kimura N, Hisatsune T, Kawabata M, et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999;284(5413):479–82.CrossRefPubMed

39.

Nakashima K, Takizawa T, Ochiai W, Yanagisawa M, Hisatsune T, Nakafuku M, et al. BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc Natl Acad Sci U S A. 2001;98(10):5868–73. doi:10.1073/pnas.101109698.PubMedCentralCrossRefPubMed

40.

Kamakura S, Oishi K, Yoshimatsu T, Nakafuku M, Masuyama N, Gotoh Y. Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol. 2004;6(6):547–54. doi:10.1038/ncb1138.CrossRefPubMed

41.

Pera EM, Ikeda A, Eivers E, De Robertis EM. Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev. 2003;17(24):3023–8. doi:10.1101/gad.1153603.PubMedCentralCrossRefPubMed

42.

Zhong Z, Wen Z, Darnell Jr JE. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264(5155):95–8.CrossRefPubMed

43.

Jouve C, Palmeirim I, Henrique D, Beckers J, Gossler A, Ish-Horowicz D, et al. Notch signalling is required for cyclic expression of the hairy-like gene HES1 in the presomitic mesoderm. Development. 2000;127(7):1421–9.PubMed

44.

Silvestri L, Caputo V, Bellacchio E, Atorino L, Dallapiccola B, Valente EM, et al. Mitochondrial import and enzymatic activity of PINK1 mutants associated to recessive parkinsonism. Hum Mol Genet. 2005;14(22):3477–92. doi:10.1093/hmg/ddi377.CrossRefPubMed

45.

Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8(9):963–70. doi:10.1038/nm747.CrossRefPubMed

46.

Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, et al. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature. 2013;497(7449):369–73. doi:10.1038/nature12069.PubMedCentralCrossRefPubMed

47.

Faiz M, Acarin L, Villapol S, Schulz S, Castellano B, Gonzalez B. Substantial migration of SVZ cells to the cortex results in the generation of new neurons in the excitotoxically damaged immature rat brain. Mol Cell Neurosci. 2008;38(2):170–82. doi:10.1016/j.mcn.2008.02.002.CrossRefPubMed

48.

Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, et al. Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci. 2006;26(24):6627–36. doi:10.1523/JNEUROSCI.0149-06.2006.CrossRefPubMed

49.

Zhang RL, Zhang ZG, Zhang L, Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience. 2001;105(1):33–41.CrossRefPubMed

50.

Costa S, Planchenault T, Charriere-Bertrand C, Mouchel Y, Fages C, Juliano S, et al. Astroglial permissivity for neuritic outgrowth in neuron-astrocyte cocultures depends on regulation of laminin bioavailability. Glia. 2002;37(2):105–13.CrossRefPubMed

51.

Tom VJ, Doller CM, Malouf AT, Silver J. Astrocyte-associated fibronectin is critical for axonal regeneration in adult white matter. J Neurosci. 2004;24(42):9282–90. doi:10.1523/JNEUROSCI.2120-04.2004.CrossRefPubMed

52.

White RE, Jakeman LB. Don’t fence me in: harnessing the beneficial roles of astrocytes for spinal cord repair. Restor Neurol Neurosci. 2008;26(2-3):197–214.PubMedCentralPubMed

53.

Shimada IS, Peterson BM, Spees JL. Isolation of locally derived stem/progenitor cells from the peri-infarct area that do not migrate from the lateral ventricle after cortical stroke. Stroke. 2010;41(9):e552–60. doi:10.1161/STROKEAHA.110.589010.PubMedCentralCrossRefPubMed

54.

Castelo-Branco G, Sousa KM, Bryja V, Pinto L, Wagner J, Arenas E. Ventral midbrain glia express region-specific transcription factors and regulate dopaminergic neurogenesis through Wnt-5a secretion. Mol Cell Neurosci. 2006;31(2):251–62. doi:10.1016/j.mcn.2005.09.014.CrossRefPubMed

55.

Wagner J, Akerud P, Castro DS, Holm PC, Canals JM, Snyder EY, et al. Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. Nat Biotechnol. 1999;17(7):653–9. doi:10.1038/10862.CrossRefPubMed

56.

Lim DA, Alvarez-Buylla A. Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc Natl Acad Sci U S A. 1999;96(13):7526–31.PubMedCentralCrossRefPubMed

57.

Episcopo FL, Tirolo C, Testa N, Caniglia S, Morale MC, Marchetti B. Reactive astrocytes are key players in nigrostriatal dopaminergic neurorepair in the MPTP mouse model of Parkinson’s disease: focus on endogenous neurorestoration. Curr Aging Sci. 2013;6(1):45–55.CrossRef

58.

O’Keeffe GC, Tyers P, Aarsland D, Dalley JW, Barker RA, Caldwell MA. Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF. Proc Natl Acad Sci U S A. 2009;106(21):8754–9.PubMedCentralCrossRefPubMed

59.

Maragakis NJ, Rothstein JD. Mechanisms of Disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol. 2006;2(12):679–89. doi:10.1038/ncpneuro0355.CrossRefPubMed

60.

Rossi D, Volterra A. Astrocytic dysfunction: insights on the role in neurodegeneration. Brain Res Bull. 2009;80(4-5):224–32. doi:10.1016/j.brainresbull.2009.07.012.CrossRefPubMed

61.

Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci. 2011;33(6):1139–51. doi:10.1111/j.1460-9568.2011.07613.x.CrossRefPubMed

62.

Taymans JM, Nkiliza A, Chartier-Harlin MC. Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson’s disease pathogenesis. Trends Mol Med. 2015;21(8):466–72. doi:10.1016/j.molmed.2015.05.004.CrossRefPubMed

63.

Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. 2010;119(1):89–105. doi:10.1007/s00401-009-0622-0.CrossRefPubMed

64.

Mullett SJ, Hinkle DA. DJ-1 knock-down in astrocytes impairs astrocyte-mediated neuroprotection against rotenone. Neurobiol Dis. 2009;33(1):28–36. doi:10.1016/j.nbd.2008.09.013.PubMedCentralCrossRefPubMed

65.

Kim B, Yang MS, Choi D, Kim JH, Kim HS, Seol W, et al. Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. PLoS ONE. 2012;7(4):e34693. doi:10.1371/journal.pone.0034693.PubMedCentralCrossRefPubMed

66.

Kim KS, Kim JS, Park JY, Suh YH, Jou I, Joe EH, et al. DJ-1 Associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes. Hum Mol Genet. 2013. doi:10.1093/hmg/ddt332.

67.

Kim JH, Choi DJ, Jeong HK, Kim J, Kim DW, Choi SY, et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1. Neurobiol Dis. 2013. doi:10.1016/j.nbd.2013.08.007.

68.

Liu GH, Qu J, Suzuki K, Nivet E, Li M, Montserrat N, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012;491(7425):603–7. doi:10.1038/nature11557.PubMedCentralCrossRefPubMed

69.

Yang W, Wang G, Wang CE, Guo X, Yin P, Gao J, et al. Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain. J Neurosci. 2015;35(21):8345–58.PubMedCentralCrossRefPubMed

70.

Kim YH, Chung JI, Woo HG, Jung YS, Lee SH, Moon CH, et al. Differential regulation of proliferation and differentiation in neural precursor cells by the Jak pathway. Stem Cells. 2010;28(10):1816–28. doi:10.1002/stem.511.CrossRefPubMed

71.

Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5. doi:10.1038/nature09663.CrossRefPubMed

Title: PINK1 expression increases during brain development and stem cell differentiation, and affects the development of GFAP-positive astrocytes
Authors: Insup Choi
Dong-Joo Choi
Haijie Yang
Joo Hong Woo
Mi-Yoon Chang
Joo Yeon Kim
Woong Sun
Sang-Myun Park
Ilo Jou
Sang-Hun Lee
Eun-Hye Joe
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Molecular Brain / Issue 1/2016
Electronic ISSN: 1756-6606
DOI: https://doi.org/10.1186/s13041-016-0186-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

PINK1 expression increases during brain development and stem cell differentiation, and affects the development of GFAP-positive astrocytes

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

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