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Mechanisms of Mutant LRRK2 Neurodegeneration

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Leucine-Rich Repeat Kinase 2 (LRRK2)

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 14))

Abstract

LRRK2 mutations are associated with the loss of neurons, that is to say toxicity, in patients and in experimental model systems. However, the mechanisms by which mutations can be linked to neurodegeneration are not fully defined. Here I will argue that mechanism in this context encompasses a variety of levels of information. Mutations or alterations in gene expression at a genetic level are one set of mechanisms that are reflected at the biochemical level likely in enhanced or persistent function of LRRK2. By impacting cellular pathways, prominently including changes in autophagy but also microtubule function, mitochondria and protein synthesis, in neurons and immune cells, the LRRK2 brain is primed for neurodegeneration in an age-dependent manner. These concepts have implications for not only modeling LRRK2 disease but also perhaps for Parkinson’s disease more generally, including the development of therapeutic modalities.

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Abbreviations

BAC:

Bacterial artificial chromosome

COR:

C-terminal of ROC

GWAS:

Genome-wide association study

LRRK2:

Leucine-rich repeat kinase 2

MAPT:

Microtubule-associated protein tau

PD:

Parkinson’s disease

ROC:

Ras of complex proteins

SNP:

Single-nucleotide polymorphism

References

  1. Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607

    Article  CAS  PubMed  Google Scholar 

  2. Paisán-Ruíz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600

    Article  PubMed  Google Scholar 

  3. Benamer HTS, de Silva R (2010) LRRK2 G2019S in the North African population: a review. Eur Neurol 63:321–325

    Article  CAS  PubMed  Google Scholar 

  4. Inzelberg R, Hassin-Baer S, Jankovic J (2014) Genetic movement disorders in patients of Jewish ancestry. JAMA Neurol 71:1567–1572

    Article  PubMed  Google Scholar 

  5. Peeraully T, Tan EK (2012) Genetic variants in sporadic Parkinson’s disease: East vs West. Parkinsonism Relat Disord 18(Suppl 1):S63–S65

    Article  PubMed  Google Scholar 

  6. Tan E-K (2007) The role of common genetic risk variants in Parkinson disease. Clin Genet 72:387–393

    Article  PubMed  Google Scholar 

  7. Bardien S, Lesage S, Brice A, Carr J (2011) Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson’s disease. Parkinsonism Relat Disord 17:501–508

    Article  PubMed  Google Scholar 

  8. Nalls MA, Pankratz N, Lill CM et al (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet 46:989–993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Singleton A, Hardy J (2011) A generalizable hypothesis for the genetic architecture of disease: pleomorphic risk loci. Hum Mol Genet 20:R158–R162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cookson MR, Hardy J, Lewis PA (2008) Genetic neuropathology of Parkinson’s disease. Int J Clin Exp Pathol 1:217–231

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lewis PA, Greggio E, Beilina A et al (2007) The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 357:668–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li X, Tan Y-C, Poulose S et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Daniëls V, Vancraenenbroeck R, Law BMH et al (2011) Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant. J Neurochem 116:304–315

    Article  PubMed  PubMed Central  Google Scholar 

  14. Guo L, Gandhi PN, Wang W et al (2007) The Parkinson’s disease-associated protein, leucine-rich repeat kinase 2 (LRRK2), is an authentic GTPase that stimulates kinase activity. Exp Cell Res 313:3658–3670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liao J, Wu C-X, Burlak C et al (2014) Parkinson disease-associated mutation R1441H in LRRK2 prolongs the “active state” of its GTPase domain. Proc Natl Acad Sci U S A 111:4055–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Greggio E, Cookson MR (2009) Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro. doi:10.1042/AN20090007

    PubMed  PubMed Central  Google Scholar 

  17. Ray S, Bender S, Kang S et al (2014) The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity. J Biol Chem 289:13042–13053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11:791–797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Greggio E, Jain S, Kingsbury A et al (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23:329–341

    Article  CAS  PubMed  Google Scholar 

  20. Smith WW, Pei Z, Jiang H et al (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9:1231–1233

    Article  CAS  PubMed  Google Scholar 

  21. 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 Off J Soc Neurosci 34:418–433

    Article  CAS  Google Scholar 

  22. Yao C, Johnson WM, Gao Y et al (2012) Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum Mol Genet 22(2):328–344. doi:10.1093/hmg/dds431

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liu Z, Hamamichi S, Lee BD et al (2011) Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson’s disease models. Hum Mol Genet 20:3933–3942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee BD, Shin J-H, VanKampen J et al (2010) Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med 16:998–1000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. West AB (2014) Ten years and counting: moving leucine-rich repeat kinase 2 inhibitors to the clinic. Mov Disord 30(2):180–189. doi:10.1002/mds.26075

    Article  PubMed  PubMed Central  Google Scholar 

  26. MacLeod D, Dowman J, Hammond R et al (2006) The familial Parkinsonism gene LRRK2 regulates neurite process morphology. Neuron 52:587–593

    Article  CAS  PubMed  Google Scholar 

  27. Nichols RJ, Dzamko N, Morrice NA et al (2010) 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization. Biochem J 430:393–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jaleel M, Nichols RJ, Deak M et al (2007) LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 405:307–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rudenko IN, Kaganovich A, Hauser DN et al (2012) The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson’s disease is a partial loss-of-function mutation. Biochem J 446:99–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rudenko IN, Chia R, Cookson MR (2012) Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson’s disease? BMC Med 10:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Biosa A, Trancikova A, Civiero L et al (2013) GTPase activity regulates kinase activity and cellular phenotypes of Parkinson’s disease-associated LRRK2. Hum Mol Genet 22:1140–1156

    Article  CAS  PubMed  Google Scholar 

  32. Ko HS, Bailey R, Smith WW et al (2009) CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity. Proc Natl Acad Sci U S A 106:2897–2902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Herzig MC, Kolly C, Persohn E et al (2011) LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum Mol Genet 20:4209–4223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Westerlund M, Belin AC, Anvret A et al (2008) Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: Implications for Parkinson’s disease. Neuroscience 152:429–436

    Article  CAS  PubMed  Google Scholar 

  35. Mandemakers W, Snellinx A, O’Neill MJ, de Strooper B (2012) LRRK2 expression is enriched in the striosomal compartment of mouse striatum. Neurobiol Dis 48:582–593

    Article  CAS  PubMed  Google Scholar 

  36. Melrose H, Lincoln S, Tyndall G et al (2006) Anatomical localization of leucine-rich repeat kinase 2 in mouse brain. Neuroscience 139:791–794

    Article  CAS  PubMed  Google Scholar 

  37. Simón-Sánchez J, Herranz-Pérez V, Olucha-Bordonau F, Pérez-Tur J (2006) LRRK2 is expressed in areas affected by Parkinson’s disease in the adult mouse brain. Eur J Neurosci 23:659–666

    Article  PubMed  Google Scholar 

  38. West AB, Cowell RM, Daher JPL et al (2014) Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 522:2465–2480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. West AB, Moore DJ, Choi C et al (2007) Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 16:223–232

    Article  CAS  PubMed  Google Scholar 

  40. Iaccarino C, Crosio C, Vitale C et al (2007) Apoptotic mechanisms in mutant LRRK2-mediated cell death. Hum Mol Genet 16:1319–1326

    Article  CAS  PubMed  Google Scholar 

  41. Li Y, Liu W, Oo TF et al (2009) Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci 12:826–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tagliaferro P, Kareva T, Oo TF et al (2015) An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease. Neurobiol Dis 82:359–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lin X, Parisiadou L, Gu X-L et al (2009) Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 64:807–827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ramonet D, Daher JPL, Lin BM et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Garcia-Miralles M, Coomaraswamy J, Häbig K et al (2015) No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts. PLoS One 10, e0118947. doi:10.1371/journal.pone.0118947

    Article  PubMed  PubMed Central  Google Scholar 

  46. Maekawa T, Mori S, Sasaki Y et al (2012) The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol Neurodegener 7:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lee J-W, Tapias V, Di Maio R et al (2015) Behavioral, neurochemical, and pathologic alterations in bacterial artificial chromosome transgenic G2019S leucine-rich repeated kinase 2 rats. Neurobiol Aging 36:505–518

    Article  CAS  PubMed  Google Scholar 

  48. Dusonchet J, Kochubey O, Stafa K et al (2011) A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J Neurosci Off J Soc Neurosci 31:907–912

    Article  CAS  Google Scholar 

  49. Tsika E, Nguyen APT, Dusonchet J et al (2015) Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson’s disease. Neurobiol Dis 77:49–61

    Article  CAS  PubMed  Google Scholar 

  50. Beccano-Kelly DA, Volta M, Munsie LN et al (2015) LRRK2 overexpression alters glutamatergic presynaptic plasticity, striatal dopamine tone, postsynaptic signal transduction, motor activity and memory. Hum Mol Genet 24:1336–1349

    Article  CAS  PubMed  Google Scholar 

  51. Yue M, Hinkle KM, Davies P et al (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol Dis 78:172–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sanchez G, Varaschin RK, Büeler H et al (2014) Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice. PLoS One 9, e94826

    Article  PubMed  PubMed Central  Google Scholar 

  53. Plowey ED, Cherra SJ, Liu Y-J, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105:1048–1056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Manzoni C, Mamais A, Dihanich S et al (2013) Pathogenic Parkinson’s disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation. Biochem Biophys Res Commun 441:862–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sánchez-Danés A, Richaud-Patin Y, Carballo-Carbajal I et al (2012) Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol Med 4:380–395

    Article  PubMed  PubMed Central  Google Scholar 

  56. Cherra SJ, Steer E, Gusdon AM et al (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182:474–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mortiboys H, Furmston R, Bronstad G et al (2015) UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology 85:846–852

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Su Y-C, Qi X (2013) Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet 22:4545–4561

    Article  CAS  PubMed  Google Scholar 

  59. Wang X, Yan MH, Fujioka H et al (2012) LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet 21:1931–1944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gehrke S, Imai Y, Sokol N, Lu B (2010) Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466:637–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Martin I, Kim JW, Lee BD et al (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease. Cell 157:472–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu G-H, Qu J, Suzuki K et al (2012) Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature 491:603–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsika E, Kannan M, Foo CS-Y et al (2014) Conditional expression of Parkinson’s disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiol Dis 71:345–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Moehle MS, Webber PJ, Tse T et al (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci Off J Soc Neurosci 32:1602–1611

    Article  CAS  Google Scholar 

  65. 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

    Article  CAS  PubMed  Google Scholar 

  66. Choi I, Kim B, Byun J-W et al (2015) LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nat Commun 6:8255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kim B, Yang M-S, Choi D et al (2012) Impaired inflammatory responses in murine lrrk2-knockdown brain microglia. PLoS One 7, e34693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Russo I, Berti G, Plotegher N et al (2015) Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-κB p50 signaling in cultured microglia cells. J Neuroinflammation 12:230

    Article  PubMed  PubMed Central  Google Scholar 

  69. Schapansky J, Nardozzi JD, Felizia F, Lavoie MJ (2014) Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet 23(16):4201–4214. doi:10.1093/hmg/ddu138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Matt SM, Johnson RW (2015) Neuro-immune dysfunction during brain aging: new insights in microglial cell regulation. Curr Opin Pharmacol 26:96–101

    Article  PubMed  PubMed Central  Google Scholar 

  71. Saha S, Ash PEA, Gowda V et al (2015) Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol Neurodegener 10:26

    Article  PubMed  PubMed Central  Google Scholar 

  72. Schapansky J, Nardozzi JD, LaVoie MJ (2015) The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson’s disease. Neuroscience 302:74–88

    Article  CAS  PubMed  Google Scholar 

  73. Jorgensen ND, Peng Y, Ho CC-Y et al (2009) The WD40 domain is required for LRRK2 neurotoxicity. PLoS One 4, e8463.1

    Article  Google Scholar 

  74. Hsu CH, Chan D, Greggio E et al (2010) MKK6 binds and regulates expression of Parkinson’s disease-related protein LRRK2. J Neurochem 112:1593–1604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Xiong Y, Yuan C, Chen R et al (2012) ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2. J Neurosci Off J Soc Neurosci 32:3877–3886

    Article  CAS  Google Scholar 

  76. Stafa K, Trancikova A, Webber PJ et al (2012) GTPase activity and neuronal toxicity of Parkinson’s disease-associated LRRK2 is regulated by ArfGAP1. PLoS Genet 8, e1002526.1

    Article  Google Scholar 

  77. Civiero L, Cirnaru MD, Beilina A et al (2015) Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. J Neurochem 135:1242–1256. doi:10.1111/jnc.13369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lavalley NJ, Slone SR, Ding H et al (2015) 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet 25(1):109–122. doi:10.1093/hmg/ddv453

    Article  PubMed  PubMed Central  Google Scholar 

  79. Cookson MR (2009) alpha-Synuclein and neuronal cell death. Mol Neurodegener 4:9

    Article  PubMed  PubMed Central  Google Scholar 

  80. Daher JPL, Volpicelli-Daley LA, Blackburn JP et al (2014) Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A 111:9289–9294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Daher JPL, Abdelmotilib HA, Hu X et al (2015) Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem 290:19433–19444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Daher JPL, Pletnikova O, Biskup S et al (2012) Neurodegenerative phenotypes in an A53T α-synuclein transgenic mouse model are independent of LRRK2. Hum Mol Genet 21:2420–2431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Herzig MC, Bidinosti M, Schweizer T et al (2012) High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain. PLoS One 7, e36581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Beilina A, Cookson MR (2015) Genes associated with Parkinson’s disease: regulation of autophagy and beyond. J Neurochem 139(Suppl 1):91–107. doi:10.1111/jnc.13266

    PubMed  Google Scholar 

  85. Goedert M (2015) NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Aβ, tau, and α-synuclein. Science 349:1255555

    Article  PubMed  Google Scholar 

  86. Wallings R, Manzoni C, Bandopadhyay R (2015) Cellular processes associated with LRRK2 function and dysfunction. FEBS J 282:2806–2826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kawakami F, Yabata T, Ohta E et al (2012) LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS One 7, e30834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lin C-H, Tsai P-I, Wu R-M, Chien C-T (2010) LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3β. J Neurosci Off J Soc Neurosci 30:13138–13149

    Article  CAS  Google Scholar 

  89. Beilina A, Rudenko IN, Kaganovich A et al (2014) Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A 111(7):2626–2631. doi:10.1073/pnas.1318306111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. MacLeod DA, Rhinn H, Kuwahara T et al (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron 77:425–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported entirely by the Intramural Research Program of the NIH and the National Institute on Aging.

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The author declares no conflicts of interest.

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  1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Room 1A116, 35 Convent Drive, Bethesda, MD, 20892-3707, USA

    Mark R. Cookson

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  1. Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece

    Hardy J. Rideout

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Cookson, M.R. (2017). Mechanisms of Mutant LRRK2 Neurodegeneration. 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_12

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