Abstract
Since its cloning and identification in 2004, considerable gains have been made in the understanding of the basic functionality of leucine-rich repeat kinase 2 (LRRK2), including its kinase and GTPase activities, its protein interactors and subcellular localization, and its expression in the CNS and peripheral tissues. However, the mechanism(s) by which expression of mutant forms of LRRK2 lead to the death of dopaminergic neurons of the ventral midbrain remains largely uncharacterized. Because of its complex domain structure, LRRK2 exhibits similarities with multiple protein families including ROCO proteins, as well as the RIP kinases. Cellular models in which mutant LRRK2 is overexpressed in neuronal-like cell lines or in primary neurons have found evidence of apoptotic cell death involving components of the extrinsic as well as intrinsic death pathways. However, since the expression of LRRK2 is comparatively quite low in ventral midbrain dopaminergic neurons, the possibility exists that non-cell autonomous signaling also contributes to the loss of these neurons. In this chapter, we will discuss the different neuronal death pathways that may be activated by mutant forms of LRRK2, guided in part by the behavior of other members of the RIP kinase protein family.
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References
Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9(10):1231–1233. doi:10.1038/nn1776
Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A 102(51):18676–18681. doi:10.1073/pnas.0508052102
West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 102(46):16842–16847. doi:10.1073/pnas.0507360102
Iaccarino C, Crosio C, Vitale C, Sanna G, Carri MT, Barone P (2007) Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 16(11):1319–1326. doi:10.1093/hmg/ddm080
Ho CC, Rideout HJ, Ribe E, Troy CM, Dauer WT (2009) The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci 29(4):1011–1016. doi:10.1523/JNEUROSCI.5175-08.2009
Kett LR, Boassa D, Ho CC, Rideout HJ, Hu J, Terada M, Ellisman M, Dauer WT (2012) LRRK2 Parkinson disease mutations enhance its microtubule association. Hum Mol Genet 21(4):890–899. doi:10.1093/hmg/ddr526
Skibinski G, Nakamura K, Cookson MR, Finkbeiner S (2014) Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci 34(2):418–433. doi:10.1523/JNEUROSCI.2712-13.2014
Chen CY, Weng YH, Chien KY, Lin KJ, Yeh TH, Cheng YP, Lu CS, Wang HL (2012) (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ 19(10):1623–1633. doi:10.1038/cdd.2012.42
Dusonchet J, Kochubey O, Stafa K, Young SM Jr, Zufferey R, Moore DJ, Schneider BL, Aebischer P (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J Neurosci 31(3):907–912. doi:10.1523/JNEUROSCI.5092-10.2011
Lee BD, Shin JH, VanKampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16(9):998–1000
Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (2011) Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6(4), e18568. doi:10.1371/journal.pone.0018568
Gillardon F, Schmid R, Draheim H (2012) Parkinson’s disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience 208:41–48
Meylan E, Tschopp J (2005) The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci 30(3):151–159. doi:10.1016/j.tibs.2005.01.003
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1(2):112–119. doi:10.1038/nchembio711
Oberst A (2015) Death in the fast lane: what’s next for necroptosis? FEBS J 283(14):2616–2625. doi:10.1111/febs.13520
Zong WX, Ditsworth D, Bauer DE, Wang ZQ, Thompson CB (2004) Alkylating DNA damage stimulates a regulated form of necrotic cell death. Genes Dev 18(11):1272–1282. doi:10.1101/gad.1199904
Wang Y, Huang ZH, Li YJ, He GW, Yu RY, Yang J, Liu WT, Li B, He QY (2016) Dynamic quantitative proteomics characterization of TNF-alpha-induced necroptosis. Apoptosis : an international journal on programmed cell death 21(12):1438–1446. doi:10.1007/s10495-016-1300-z
Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451. doi:10.1038/onc.2008.310
Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102(34):12005–12010. doi:10.1073/pnas.0505294102
Laster SM, Wood JG, Gooding LR (1988) Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol 141(8):2629–2634
Vercammen D, Beyaert R, Denecker G, Goossens V, Van Loo G, Declercq W, Grooten J, Fiers W, Vandenabeele P (1998) Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J Exp Med 187(9):1477–1485
Moriwaki K, Bertin J, Gough PJ, Chan FK (2015) A RIPK3-caspase 8 complex mediates atypical pro-IL-1beta processing. J Immunol 194(4):1938–1944. doi:10.4049/jimmunol.1402167
Feng S, Yang Y, Mei Y, Ma L, Zhu DE, Hoti N, Castanares M, Wu M (2007) Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal 19(10):2056–2067. doi:10.1016/j.cellsig.2007.05.016
Lin Y, Devin A, Rodriguez Y, Liu ZG (1999) Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 13(19):2514–2526
Orozco S, Yatim N, Werner MR, Tran H, Gunja SY, Tait SW, Albert ML, Green DR, Oberst A (2014) RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ 21(10):1511–1521. doi:10.1038/cdd.2014.76
Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R (2009) LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum Mol Genet 18(21):4022–4034
Reynolds A, Doggett EA, Riddle SM, Lebakken CS, Nichols RJ (2014) LRRK2 kinase activity and biology are not uniformly predicted by its autophosphorylation and cellular phosphorylation site status. Front Mol Neurosci 7:54. doi:10.3389/fnmol.2014.00054
Siegel RM, Martin DA, Zheng L, Ng SY, Bertin J, Cohen J, Lenardo MJ (1998) Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141(5):1243–1253
Wu JR, Wang J, Zhou SK, Yang L, Yin JL, Cao JP, Cheng YB (2015) Necrostatin-1 protection of dopaminergic neurons. Neural Regen Res 10(7):1120–1124. doi:10.4103/1673-5374.160108
Houlden H, Singleton AB (2012) The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol 124(3):325–338. doi:10.1007/s00401-012-1013-5
Vitner EB, Salomon R, Farfel-Becker T, Meshcheriakova A, Ali M, Klein AD, Platt FM, Cox TM, Futerman AH (2014) RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat Med 20(2):204–208. doi:10.1038/nm.3449
Herzig MC, Kolly C, Persohn E, Theil D, Schweizer T, Hafner T, Stemmelen C, Troxler TJ, Schmid P, Danner S, Schnell CR, Mueller M, Kinzel B, Grevot A, Bolognani F, Stirn M, Kuhn RR, Kaupmann K, van der Putten PH, Rovelli G, Shimshek DR (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 20(21):4209–4223. doi:10.1093/hmg/ddr348
Liu Q, Qiu J, Liang M, Golinski J, van Leyen K, Jung JE, You Z, Lo EH, Degterev A, Whalen MJ (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5, e1084. doi:10.1038/cddis.2014.69
Matsuzawa Y, Oshima S, Nibe Y, Kobayashi M, Maeyashiki C, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Watanabe M (2015) RIPK3 regulates p62-LC3 complex formation via the caspase-8-dependent cleavage of p62. Biochem Biophys Res Commun 456(1):298–304. doi:10.1016/j.bbrc.2014.11.075
Hou W, Han J, Lu C, Goldstein LA, Rabinowich H (2010) Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy 6(7):891–900. doi:10.4161/auto.6.7.13038
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10(5):608–614. doi:10.1038/nn1885
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. doi:10.1038/nn1876
Rojas F, Cortes N, Abarzua S, Dyrda A, van Zundert B (2014) Astrocytes expressing mutant SOD1 and TDP43 trigger motoneuron death that is mediated via sodium channels and nitroxidative stress. Front Cell Neurosci 8:24. doi:10.3389/fncel.2014.00024
Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97(3):687–696. doi:10.1111/j.1471-4159.2006.03742.x
Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, Ikiz B, Hoffmann L, Koolen M, Nagata T, Papadimitriou D, Nagy P, Mitsumoto H, Kariya S, Wichterle H, Henderson CE, Przedborski S (2014) Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81(5):1001–1008. doi:10.1016/j.neuron.2014.01.011
Fricker M, Vilalta A, Tolkovsky AM, Brown GC (2013) Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J Biol Chem 288(13):9145–9152. doi:10.1074/jbc.M112.427880
Zhu S, Zhang Y, Bai G, Li H (2011) Necrostatin-1 ameliorates symptoms in R6/2 transgenic mouse model of Huntington’s disease. Cell Death Dis 2, e115. doi:10.1038/cddis.2010.94
Dondelinger Y, Jouan-Lanhouet S, Divert T, Theatre E, Bertin J, Gough PJ, Giansanti P, Heck AJ, Dejardin E, Vandenabeele P, Bertrand MJ (2015) NF- κB-independent role of IKκ/IKKβ in Preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol Cell 60(1):63–76. doi:10.1016/j.molcel.2015.07.032
Dzamko N, Inesta-Vaquera F, Zhang J, Xie C, Cai H, Arthur S, Tan L, Choi H, Gray N, Cohen P, Pedrioli P, Clark K, Alessi DR (2012) The IκB kinase family phosphorylates the Parkinson’s disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS One 7(6), e39132. doi:10.1371/journal.pone.0039132
Chia R, Haddock S, Beilina A, Rudenko IN, Mamais A, Kaganovich A, Li Y, Kumaran R, Nalls MA, Cookson MR (2014) Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. Nat Commun 5:5827. doi:10.1038/ncomms6827
Dzamko N, Deak M, Hentati F, Reith AD, Prescott AR, Alessi DR, Nichols RJ (2010) Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J 430(3):405–413
Li X, Wang QJ, Pan N, Lee S, Zhao Y, Chait BT, Yue Z (2011) Phosphorylation-dependent 14-3-3 binding to LRRK2 is impaired by common mutations of familial Parkinson’s disease. PLoS One 6(3), e17153. doi:10.1371/journal.pone.0017153
Nichols RJ, Dzamko N, Morrice NA, Campbell DG, Deak M, Ordureau A, Macartney T, Tong Y, Shen J, Prescott AR, Alessi DR (2010) 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization. Biochem J 430(3):393–404
Yang JK (2015) Death effecter domain for the assembly of death-inducing signaling complex. Apoptosis 20(2):235–239. doi:10.1007/s10495-014-1060-6
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, Damko E, Moquin D, Walz T, McDermott A, Chan FK, Wu H (2012) The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150(2):339–350. doi:10.1016/j.cell.2012.06.019
Alappat EC, Feig C, Boyerinas B, Volkland J, Samuels M, Murmann AE, Thorburn A, Kidd VJ, Slaughter CA, Osborn SL, Winoto A, Tang WJ, Peter ME (2005) Phosphorylation of FADD at serine 194 by CKIα regulates its nonapoptotic activities. Mol Cell 19(3):321–332. doi:10.1016/j.molcel.2005.06.024
Jang MS, Lee SJ, Kim CJ, Lee CW, Kim E (2011) Phosphorylation by polo-like kinase 1 induces the tumor-suppressing activity of FADD. Oncogene 30(4):471–481. doi:10.1038/onc.2010.423
Jang MS, Lee SJ, Kang NS, Kim E (2011) Cooperative phosphorylation of FADD by Aur-A and Plk1 in response to taxol triggers both apoptotic and necrotic cell death. Cancer Res 71(23):7207–7215. doi:10.1158/0008-5472.CAN-11-0760
Su YC, Guo X, Qi X (2015) Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy. Biochim Biophys Acta 1852(1):12–21. doi:10.1016/j.bbadis.2014.11.009
De Chiara G, Marcocci ME, Torcia M, Lucibello M, Rosini P, Bonini P, Higashimoto Y, Damonte G, Armirotti A, Amodei S, Palamara AT, Russo T, Garaci E, Cozzolino F (2006) Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. J Biol Chem 281(30):21353–21361. doi:10.1074/jbc.M511052200
Ho DH, Kim H, Kim J, Sim H, Ahn H, Kim J, Seo H, Chung KC, Park BJ, Son I, Seol W (2015) Leucine-Rich Repeat Kinase 2 (LRRK2) phosphorylates p53 and induces p21(WAF1/CIP1) expression. Mol Brain 8:54. doi:10.1186/s13041-015-0145-7
Dietrich P, Rideout HJ, Wang Q, Stefanis L (2003) Lack of p53 delays apoptosis, but increases ubiquitinated inclusions, in proteasomal inhibitor-treated cultured cortical neurons. Mol Cell Neurosci 24(2):430–441
Mogi M, Kondo T, Mizuno Y, Nagatsu T (2007) p53 protein, interferon-gamma, and NF-κB levels are elevated in the parkinsonian brain. Neurosci Lett 414(1):94–97. doi:10.1016/j.neulet.2006.12.003
Nair VD (2006) Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson’s disease. Apoptosis 11(6):955–966. doi:10.1007/s10495-006-6316-3
Liang SH, Clarke MF (2001) Regulation of p53 localization. Eur J Biochem 268(10):2779–2783
Lin Y, Ma W, Benchimol S (2000) Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet 26(1):122–127. doi:10.1038/79102
Cui J, Yu M, Niu J, Yue Z, Xu Z (2011) Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system. Biosci Rep 31(5):429–437. doi:10.1042/BSR20100127
Moehle MS, Daher JP, Hull TD, Boddu R, Abdelmotilib HA, Mobley J, Kannarkat GT, Tansey MG, West AB (2015) The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. Hum Mol Genet 24(15):4250–4267. doi:10.1093/hmg/ddv157
Moehle MS, Webber PJ, Tse T, Sukar N, Standaert DG, DeSilva TM, Cowell RM, West AB (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci 32(5):1602–1611. doi:10.1523/JNEUROSCI.5601-11.2012
Ofengeim D, Yuan J (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nature reviews Molecular cell biology 14 (11):727–736. doi:10.1038/nrm3683
Kearney CJ, Cullen SP, Tynan GA, Henry CM, Clancy D, Lavelle EC, Martin SJ (2015) Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production. Cell Death Differ 22(8):1313–1327. doi:10.1038/cdd.2014.222
Davies P, Hinkle KM, Sukar NN, Sepulveda B, Mesias R, Serrano G, Alessi DR, Beach TG, Benson DL, White CL, Cowell RM, Das SS, West AB, Melrose HL (2013) Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies. Biochem J 453(1):101–113. doi:10.1042/BJ20121742
Lee H, Melrose HL, Yue M, Pare JF, Farrer MJ, Smith Y (2010) Lrrk2 localization in the primate basal ganglia and thalamus: a light and electron microscopic analysis in monkeys. Exp Neurol 224(2):438–447. doi:10.1016/j.expneurol.2010.05.004
Fraser KB, Moehle MS, Daher JP, Webber PJ, Williams JY, Stewart CA, Yacoubian TA, Cowell RM, Dokland T, Ye T, Chen D, Siegal GP, Galemmo RA, Tsika E, Moore DJ, Standaert DG, Kojima K, Mobley JA, West AB (2013) LRRK2 secretion in exosomes is regulated by 14-3-3. Hum Mol Genet 22(24):4988–5000. doi:10.1093/hmg/ddt346
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Rideout, H.J., Re, D.B. (2017). LRRK2 and the “LRRKtosome” at the Crossroads of Programmed Cell Death: Clues from RIP Kinase Relatives. In: Rideout, H. (eds) Leucine-Rich Repeat Kinase 2 (LRRK2). Advances in Neurobiology, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-49969-7_10
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