Top

Published in:

Open Access 01-12-2009 | Research article

Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation

Authors: Javorina Milosevic, Sigrid C Schwarz, Vera Ogunlade, Anne K Meyer, Alexander Storch, Johannes Schwarz

Published in: Molecular Neurodegeneration | Issue 1/2009

Abstract

Despite a comprehensive mapping of the Parkinson's disease (PD)-related mRNA and protein leucine-rich repeat kinase 2 (LRRK2) in the mammalian brain, its physiological function in healthy individuals remains enigmatic. Based on its structural features and kinase properties, LRRK2 may interact with other proteins involved in signalling pathways. Here, we show a widespread LRRK2 mRNA and/or protein expression in expanded or differentiated human mesencephalic neural progenitor cells (hmNPCs) and in post-mortem substantia nigra PD patients. Using small interfering RNA duplexes targeting LRRK2 in hmNPCs following their differentiation into glia and neurons, we observed a reduced number of dopaminergic neurons due to apoptosis in LRRK2 knockdown samples. LRRK2-deficient hmNPCs exhibited elevated cell cycle- and cell death-related markers. In conclusion, a reduction of LRRK2 expression in hmNPCs severely impaired dopaminergic differentiation and/or survival of dopaminergic neurons most likely via preserving or reactivating the cell cycle.

Available only for authorised users

Klein C, Schlossmacher MG: The genetics of Parkinson disease: implications for neurological care. Nat Clin Pract Neuro. 2006, 2: 136-146. 10.1038/ncpneuro0126.CrossRef

Gasser T: Genetics of Parkinson's disease. Curr Opin Neurol. 2005, 18 (4): 363-369. 10.1097/01.wco.0000170951.08924.3d.CrossRefPubMed

Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, Brug van der M, de Munain AL, Aparicio S, Gil AM, Khan N, et al: Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease. Neuron. 2004, 44 (4): 595-600. 10.1016/j.neuron.2004.10.023.CrossRefPubMed

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, et al: Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology. Neuron. 2004, 44 (4): 601-607. 10.1016/j.neuron.2004.11.005.CrossRefPubMed

West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM: From The Cover: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proceedings of the National Academy of Sciences. 2005, 102: 16842-16847. 10.1073/pnas.0507360102.CrossRef

Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proceedings of the National Academy of Sciences. 2005, 102: 18676-18681. 10.1073/pnas.0508052102.CrossRef

Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P: Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet. 2007, 16: 1319-1326. 10.1093/hmg/ddm080.CrossRefPubMed

Taymans J-M, Haute Van den C, Baekelandt V: Distribution of PINK1 and LRRK2 in rat and mouse brain. J Neurochem. 2006, 98 (3): 951-961. 10.1111/j.1471-4159.2006.03919.x.CrossRefPubMed

Higashi S, Biskup S, West AB, Trinkaus D, Dawson VL, Faull RLM, Waldvogel HJ, Arai H, Dawson TM, Moore DJ, Emson PC: Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Res. 2007, 1155: 208-219. 10.1016/j.brainres.2007.04.034.CrossRefPubMed

10.

Miklossy J, Arai T, Guo JP, Klegeris A, Yu S, McGeer EG, McGeer PL: LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol. 2006, 65 (10): 953-963. 10.1097/01.jnen.0000235121.98052.54.CrossRefPubMed

11.

Dagmar G, Westerlund M, Carmine A, Lindqvist E, Sydow O, Olson L: LRRK2 expression linked to dopamine-innervated areas. Annals of Neurology. 2006, 59: 714-719. 10.1002/ana.20808.CrossRef

12.

Biskup S, Moore D, Rea A, Lorenz-Deperieux B, Coombes C, Dawson V, Dawson T, West A: Dynamic and redundant regulation of LRRK2 and LRRK1 expression. BMC Neuroscience. 2007, 8: 102-10.1186/1471-2202-8-102.PubMedCentralCrossRefPubMed

13.

Hartmann A, Hunot Sp, Michel PP, Muriel M-P, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel Hln, Srinivasan A, Ruberg M, et al: Caspase-3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America. 2000, 97: 2875-2880. 10.1073/pnas.040556597.PubMedCentralCrossRefPubMed

14.

Milosevic J, Maisel M, Wegner F, Leuchtenberger J, Wenger RH, Gerlach M, Storch A, Schwarz J: Lack of Hypoxia-Inducible Factor-1{alpha} Impairs Midbrain Neural Precursor Cells Involving Vascular Endothelial Growth Factor Signaling. J Neurosci. 2007, 27: 412-421. 10.1523/JNEUROSCI.2482-06.2007.CrossRefPubMed

15.

Levine AJ: p53, the Cellular Gatekeeper for Growth and Division. Cell. 1997, 88: 323-331. 10.1016/S0092-8674(00)81871-1.CrossRefPubMed

16.

Shieh S-Y, Ikeda M, Taya Y, Prives C: DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2. Cell. 1997, 91: 325-334. 10.1016/S0092-8674(00)80416-X.CrossRefPubMed

17.

Honda R, Tanaka H, Yasuda H: Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Letters. 1997, 420: 25-27. 10.1016/S0014-5793(97)01480-4.CrossRefPubMed

18.

Duan W, Zhu X, Ladenheim B, Yu Q-S, Guo Z, Oyler J, Cutler RG, Cadet JL, H GN, Mattson MP: p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Annals of Neurology. 2002, 52: 597-606. 10.1002/ana.10350.CrossRefPubMed

19.

Kilker RL, Planas-Silva MD: Cyclin D1 Is Necessary for Tamoxifen-Induced Cell Cycle Progression in Human Breast Cancer Cells. Cancer Res. 2006, 66: 11478-11484. 10.1158/0008-5472.CAN-06-1755.CrossRefPubMed

20.

Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A: Structure of the RPA trimerization core and its role in the multistep DNA-binding mechanism of RPA. Embo J. 2002, 21 (7): 1855-1863. 10.1093/emboj/21.7.1855.PubMedCentralCrossRefPubMed

21.

Tominaga K, Morisaki H, Kaneko Y, Fujimoto A, Tanaka T, Ohtsubo M, Hirai M, Okayama H, Ikeda K, Nakanishi M: Role of Human Cds1 (Chk2) Kinase in DNA Damage Checkpoint and Its Regulation by p53. J Biol Chem. 1999, 274: 31463-31467. 10.1074/jbc.274.44.31463.CrossRefPubMed

22.

Murray AW, Solomon MJ, Kirschner MW: The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature. 1989, 339: 280-286. 10.1038/339280a0.CrossRefPubMed

23.

Maity A, McKenna WG, Muschel RJ: Evidence for post-transcriptional regulation of cyclin B1 mRNA in the cell cycle and following irradiation in HeLa cells. EMBO J. 1995, 14 (3): 603-609.PubMedCentralPubMed

24.

Alegre-Abarrategui J, Ansorge O, Esiri M, Wade-Martins R: LRRK2 is a component of granular alpha-synuclein pathology in the brainstem of Parkinson's disease. Neuropathology and Applied Neurobiology. 2008, 34: 272-283. 10.1111/j.1365-2990.2007.00888.x.PubMedCentralCrossRefPubMed

25.

Melrose HL, Kent CB, Taylor JP, Dachsel JC, Hinkle KM, Lincoln SJ, Mok SS, Culvenor JG, Masters CL, Tyndall GM, et al: A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. Neuroscience. 2007, 147: 1047-1058. 10.1016/j.neuroscience.2007.05.027.CrossRefPubMed

26.

Häbig K, Walter M, Poths S, Riess O, Bonin M: RNA interference of LRRK2-microarray expression analysis of a Parkinson's disease key player. neurogenetics. 2008, 9: 83-94. 10.1007/s10048-007-0114-0.CrossRefPubMed

27.

Mogi M, Kondo T, Mizuno Y, Nagatsu T: p53 protein, interferon-[gamma], and NF-[kappa]B levels are elevated in the parkinsonian brain. Neuroscience Letters. 2007, 414: 94-97. 10.1016/j.neulet.2006.12.003.CrossRefPubMed

28.

Nair VD, McNaught KS, Gonzalez-Maeso J, Sealfon SC, Olanow CW: p53 Mediates Nontranscriptional Cell Death in Dopaminergic Cells in Response to Proteasome Inhibition. J Biol Chem. 2006, 281: 39550-39560. 10.1074/jbc.M603950200.CrossRefPubMed

29.

Schmetsdorf S, Gärtner U, Arendt T: Expression of cell cycle-related proteins in developing and adult mouse hippocampus. International Journal of Developmental Neuroscience. 2005, 23: 101-112. 10.1016/j.ijdevneu.2004.07.019.CrossRefPubMed

30.

Koeller HB, Ross ME, Glickstein SB: Cyclin D1 in excitatory neurons of the adult brain enhances kainate-induced neurotoxicity. Neurobiology of Disease. 2008, 31: 230-241. 10.1016/j.nbd.2008.04.010.PubMedCentralCrossRefPubMed

31.

Husseman JW, Nochlin D, Vincent I: Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiology of Aging. 2000, 21: 815-828. 10.1016/S0197-4580(00)00221-9.CrossRefPubMed

32.

Mosch B, Morawski M, Mittag A, Lenz D, Tarnok A, Arendt T: Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease. J Neurosci. 2007, 27: 6859-6867. 10.1523/JNEUROSCI.0379-07.2007.CrossRefPubMed

33.

Höglinger GU, Breunig JJ, Depboylu C, Rouaux C, Michel PP, Alvarez-Fischer D, Boutillier A-L, DeGregori J, Oertel WH, Rakic P, et al: The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proceedings of the National Academy of Sciences. 2007, 104: 3585-3590. 10.1073/pnas.0611671104.CrossRef

34.

Yang Y, Geldmacher DS, Herrup K: DNA Replication Precedes Neuronal Cell Death in Alzheimer's Disease. J Neurosci. 2001, 21: 2661-2668.PubMed

35.

Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB: TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model. Current Biology. 2006, 16: 230-241. 10.1016/j.cub.2005.12.042.CrossRefPubMed

36.

Zhao M, Momma S, Delfani K, Carlén M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisén J, Janson AM: Evidence for neurogenesis in the adult mammalian substantia nigra. Proceedings of the National Academy of Sciences of the United States of America. 2003, 100: 7925-7930. 10.1073/pnas.1131955100.PubMedCentralCrossRefPubMed

37.

Frielingsdorf H, Schwarz K, Brundin P, Mohapel P: No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proceedings of the National Academy of Sciences of the United States of America. 2004, 101: 10177-10182. 10.1073/pnas.0401229101.PubMedCentralCrossRefPubMed

38.

Hermann A, Maisel M, Wegner F, Liebau S, Kim DW, Gerlach M, Schwarz J, Kim KS, Storch A: Multipotent Neural Stem Cells from the Adult Tegmentum with Dopaminergic Potential Develop Essential Properties of Functional Neurons. Stem Cells. 2006, 24: 949-964. 10.1634/stemcells.2005-0192.CrossRefPubMed

39.

Hermann A, Storch A: Endogenous Regeneration in Parkinson's Disease: Do We Need Orthotopic Dopaminergic Neurogenesis?. Stem Cells. 2008, 26: 2749-2752. 10.1634/stemcells.2008-0567.CrossRefPubMed

40.

Biskup S, West AB: Zeroing in on LRRK2-linked pathogenicmechanisms in Parkinson's disease. Biochimica et BiophysicaActa (BBA) – Molecular Basis of Disease

41.

Liou AKF, Leak RK, Li L, Zigmond MJ: Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway. Neurobiology of Disease. 2008, 32: 116-124. 10.1016/j.nbd.2008.06.016.PubMedCentralCrossRefPubMed

42.

Milosevic J, Schwarz SC, Krohn K, Poppe M, Storch A, Schwarz J: Low atmospheric oxygen avoids maturation, senescence and cell death of murine mesencephalic neural precursors. J Neurochem. 2005, 92: 718-729. 10.1111/j.1471-4159.2004.02893.x.CrossRefPubMed

43.

Storch A, Paul G, Csete M, Boehm BO, Carvey PM, Kupsch A, Schwarz J: Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells. Exp Neurol. 2001, 170: 317-325. 10.1006/exnr.2001.7706.CrossRefPubMed

44.

Dieterlen M-T, Wegner F, Schwarz SC, Milosevic J, Schneider B, Busch M, Römuß U, Brandt A, Storch A, Schwarz J: Non-viral gene transfer by nucleofection allows stable gene expression in human neural progenitor cells. Journal of Neuroscience Methods. 2009, 178: 15-23. 10.1016/j.jneumeth.2008.11.007.CrossRefPubMed

45.

Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed

46.

Milosevic J, Brandt A, Roemuss U, Arnold A, Wegner F, Schwarz SC, Storch A, Zimmermann H, Schwarz J: Uracil nucleotides stimulate human neural precursor cell proliferation and dopaminergic differentiation: involvement of MEK/ERK signalling. J Neurochem. 2006, 99 (3): 913-923. 10.1111/j.1471-4159.2006.04132.x.CrossRefPubMed

Title: Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation
Authors: Javorina Milosevic
Sigrid C Schwarz
Vera Ogunlade
Anne K Meyer
Alexander Storch
Johannes Schwarz
Publication date: 01-12-2009
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2009
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/1750-1326-4-25

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Emerging role of LRRK2 in human neural progenitor cell cycle progression, survival and differentiation

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2009

Calnuc plays a role in dynamic distribution of Gαi but not Gβ subunits and modulates ACTH secretion in AtT-20 neuroendocrine secretory cells

Calcium signaling in neurodegeneration

Novel cerebrovascular pathology in mice fed a high cholesterol diet

An exo-cell assay for examining real-time γ-secretase activity and inhibition

PGC-1alphaas modifier of onset age in Huntington disease

Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells