1,272
Views
33
CrossRef citations to date
0
Altmetric
Review

Targeting LRRK2 in Parkinson’s disease: an update on recent developments

&
Pages 601-610 | Received 10 Jan 2017, Accepted 25 Apr 2017, Published online: 15 May 2017

References

  • Haugarvoll K, Rademakers R, Kachergus JM, et al. Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease. Neurology. 2008;70:1456–1460.
  • Healy DG, Falchi M, O’Sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583–590.
  • Foo JN, Chung SJ, Tan LC, et al. Linking a genome-wide association study signal to a LRRK2 coding variant in Parkinson’s disease. Mov Disord. 2016;31:484–487.
  • Foo JN, Tan LC, Irwan ID, et al. Genome-wide association study of Parkinson’s disease in East Asians. Hum Mol Genet. 2017;26:226–232.
  • Kumar PM, Paing SS, Li H, et al. Differential effect of caffeine intake in subjects with genetic susceptibility to Parkinson’s disease. Sci Rep. 2015;5:15492.
  • Oosterveld LP, Allen JC Jr., Ng EY, et al. Greater motor progression in patients with Parkinson disease who carry LRRK2 risk variants. Neurology. 2015;85:1039–1042.
  • Tan EK. Rare and common LRRK2 exonic variants in Parkinson’s disease. Lancet Neurol. 2011;10:869–870.
  • Buhat DM, Tan EK. Genetic testing of LRRK2 in Parkinson’s disease: is there a clinical role? Parkinsonism Relat Disord. 2014;20(Suppl 1):S54–6.
  • Infante J, Prieto C, Sierra M, et al. Comparative blood transcriptome analysis in idiopathic and LRRK2 G2019S-associated Parkinson’s disease. Neurobiol Aging. 2016;38(214):e1–5.
  • Sheng Z, Zhang S, Bustos D, et al. Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med. 2012;4:164ra1.
  • West AB, Moore DJ, Biskup S, et al. Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005;102:16842–16847.
  • Angeles DC, Ho P, Dymock BW, et al. Antioxidants inhibit neuronal toxicity in Parkinson’s disease-linked LRRK2. Ann Clin Transl Neurol. 2016;3:288–294.
  • Lu YW, Tan EK. Molecular biology changes associated with LRRK2 mutations in Parkinson’s disease. J Neurosci Res. 2008;86:1895–1901.
  • Angeles DC, Ho P, Chua LL, et al. Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Hum Mol Genet. 2014;23:3157–3165.
  • Chan SL, Angeles DC, Tan EK. Targeting leucine-rich repeat kinase 2 in Parkinson’s disease. Expert Opin Ther Targets. 2013;17:1471–1482.
  • Skibinski G, Nakamura K, Cookson MR, et al. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci. 2014;34:418–433.
  • Doggett EA, Zhao J, Mork CN, et al. Phosphorylation of LRRK2 serines 955 and 973 is disrupted by Parkinson’s disease mutations and LRRK2 pharmacological inhibition. J Neurochem. 2012;120:37–45.
  • Nichols RJ, Dzamko N, Morrice NA, et al. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease-associated mutations and regulates cytoplasmic localization. Biochem J. 2010;430:393–404.
  • Dzamko N, Deak M, Hentati F, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J. 2010;430:405–413.
  • Dzamko N, Gysbers AM, Bandopadhyay R, et al. LRRK2 levels and phosphorylation in Parkinson’s disease brain and cases with restricted Lewy bodies. Mov Disord. 2017;32:423–432.
  • Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3:1301–1306.
  • Brooks AI, Chadwick CA, Gelbard HA, et al. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 1999;823:1–10.
  • Carlsson A, Lindqvist M, Magnusson T. 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature. 1957;180:1200.
  • Heikkila RE, Nicklas WJ, Vyas I, et al. Dopaminergic toxicity of rotenone and the 1-methyl-4-phenylpyridinium ion after their stereotaxic administration to rats: implication for the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Neurosci Lett. 1985;62:389–394.
  • Przedborski S, Jackson-Lewis V, Naini AB, et al. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. J Neurochem. 2001;76:1265–1274.
  • Low K, Aebischer P. Use of viral vectors to create animal models for Parkinson’s disease. Neurobiol Dis. 2012;48:189–201.
  • Lee BD, Shin JH, VanKampen J, et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat Med. 2010;16:998–1000.
  • Dusonchet J, Kochubey O, Stafa K, et al. A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J Neurosci. 2011;31:907–912.
  • Tsika E, Nguyen AP, Dusonchet J, et al. Adenoviral-mediated expression of G2019S LRRK2 induces striatal pathology in a kinase-dependent manner in a rat model of Parkinson’s disease. Neurobiol Dis. 2015;77:49–61.
  • Palomo-Garo C, Gomez-Galvez Y, Garcia C, et al. Targeting the cannabinoid CB2 receptor to attenuate the progression of motor deficits in LRRK2-transgenic mice. Pharmacol Res. 2016;110:181–192.
  • Hinkle KM, Yue M, Behrouz B, et al. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener. 2012;7:25.
  • Ness D, Ren Z, Gardai S, et al. Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. Plos One. 2013;8:e66164.
  • Baptista MA, Dave KD, Frasier MA, et al. Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. Plos One. 2013;8:e80705.
  • Deng X, Dzamko N, Prescott A, et al. Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2. Nat Chem Biol. 2011;7:203–205.
  • Fell MJ, Mirescu C, Basu K, et al. MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. J Pharmacol Exp Ther. 2015;355:397–409.
  • Daher JP, Abdelmotilib HA, Hu X, et al. Leucine-rich repeat kinase 2 (LRRK2) pharmacological inhibition abates alpha-synuclein gene-induced neurodegeneration. J Biol Chem. 2015;290:19433–19444.
  • Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–872.
  • Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–1920.
  • Lin T, Ambasudhan R, Yuan X, et al. A chemical platform for improved induction of human iPSCs. Nat Methods. 2009;6:805–808.
  • Okita K, Nakagawa M, Hyenjong H, et al. Generation of mouse induced pluripotent stem cells without viral vectors. Science. 2008;322:949–953.
  • Stadtfeld M, Nagaya M, Utikal J, et al. Induced pluripotent stem cells generated without viral integration. Science. 2008;322:945–949.
  • Warren L, Manos PD, Ahfeldt T, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell. 2010;7:618–630.
  • Chambers SM, Fasano CA, Papapetrou EP, et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009;27:275–280.
  • Han DW, Tapia N, Hermann A, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell Stem Cell. 2012;10:465–472.
  • Thier M, Worsdorfer P, Lakes YB, et al. Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell. 2012;10:473–479.
  • Nguyen HN, Byers B, Cord B, et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell. 2011;8:267–280.
  • Su YC, Qi X. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet. 2013;22:4545–4561.
  • Orenstein SJ, Kuo SH, Tasset I, et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci. 2013;16:394–406.
  • Sanders LH, Laganiere J, Cooper O, et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: reversal by gene correction. Neurobiol Dis. 2014;62:381–386.
  • Schwab AJ, Ebert AD. Neurite aggregation and calcium dysfunction in ipsc-derived sensory neurons with Parkinson’s disease-related LRRK2 G2019S mutation. Stem Cell Reports. 2015;5:1039–1052.
  • De Maturana L, Lang R,V, Zubiarrain A, et al. Mutations in LRRK2 impair NF-kappaB pathway in iPSC-derived neurons. J Neuroinflammation. 2016;13:295.
  • Ohta E, Nihira T, Uchino A, et al. I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3beta signaling pathway. Hum Mol Genet. 2015;24:4879–4900.
  • Cooper O, Seo H, Andrabi S, et al. Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson’s disease. Sci Transl Med. 2012;4:141ra90.
  • Liu GH, Qu J, Suzuki K, et al. Progressive degeneration of human neural stem cells caused by pathogenic LRRK2. Nature. 2012;491:603–607.
  • Choi HG, Zhang J, Deng X, et al. Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett. 2012;3:658–662.
  • Reith AD, Bamborough P, Jandu K, et al. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012;22:5625–5629.
  • Zhang J, Deng X, Choi HG, et al. Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012;22:1864–1869.
  • Hatcher JM, Zhang J, Choi HG, et al. Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor. ACS Med Chem Lett. 2015;6:584–589.
  • Estrada AA, Liu X, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2012;55:9416–9433.
  • Fuji RN, Flagella M, Baca M, et al. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015;7:273ra15.
  • Estrada AA, Chan BK, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014;57:921–936.
  • Henderson JL, Kormos BL, Hayward MM, et al. Discovery and preclinical profiling of 3-[4-(Morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. J Med Chem. 2015;58:419–432.
  • Friedman LG, Lachenmayer ML, Wang J, et al. Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of alpha-synuclein and LRRK2 in the brain. J Neurosci. 2012;32:7585–7593.
  • Tong Y, Yamaguchi H, Giaime E, et al. Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death in aged mice. Proc Natl Acad Sci U S A. 2010;107:9879–9884.
  • Manzoni C, Mamais A, Roosen DA, et al. mTOR independent regulation of macroautophagy by leucine rich repeat kinase 2 via beclin-1. Sci Rep. 2016;6:35106.
  • Park S, Han S, Choi I, et al. Interplay between leucine-rich repeat kinase 2 (LRRK2) and p62/SQSTM-1 in selective autophagy. Plos One. 2016;11:e0163029.
  • Lobbestael E, Civiero L, De Wit T, et al. Pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation. Sci Rep. 2016;6:33897.
  • Schapansky J, Nardozzi JD, Felizia F, et al. Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum Mol Genet. 2014;23:4201–4214.
  • MacLeod DA, Rhinn H, Kuwahara T, et al. RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson’s disease risk. Neuron. 2013;77:425–439.
  • Rivero-Rios P, Gomez-Suaga P, Fernandez B, et al. Alterations in late endocytic trafficking related to the pathobiology of LRRK2-linked Parkinson’s disease. Biochem Soc Trans. 2015;43:390–395.
  • Carney DS, Davies BA, Horazdovsky BF. Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons. Trends Cell Biol. 2006;16:27–35.
  • Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol. 2003;161:609–624.
  • Shin N, Jeong H, Kwon J, et al. LRRK2 regulates synaptic vesicle endocytosis. Exp Cell Res. 2008;314:2055–2065.
  • Rink J, Ghigo E, Kalaidzidis Y, et al. Rab conversion as a mechanism of progression from early to late endosomes. Cell. 2005;122:735–749.
  • Dodson MW, Zhang T, Jiang C, et al. Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning. Hum Mol Genet. 2012;21:1350–1363.
  • Steger M, Tonelli F, Ito G, et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5.
  • Nichols RJ, Dzamko N, Hutti JE, et al. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson’s disease. Biochem J. 2009;424:47–60.
  • Youle RJ, Van Der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–1065.
  • Wang X, Yan MH, Fujioka H, et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet. 2012;21:1931–1944.
  • Niu J, Yu M, Wang C, et al. Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via dynamin-like protein. J Neurochem. 2012;122:650–658.
  • Yang S, Xia C, Li S, et al. Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model. Cell Death Dis. 2014;5:e1217.
  • Stafa K, Tsika E, Moser R, et al. Functional interaction of Parkinson’s disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet. 2014;23:2055–2077.
  • Hsieh CH, Shaltouki A, Gonzalez AE, et al. Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell. 2016;19:709–724.
  • Choi I, Kim B, Byun JW, et al. LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nat Commun. 2015;6:8255.
  • Godena VK, Brookes-Hocking N, Moller A, et al. Increasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations. Nat Commun. 2014;5:5245.
  • Civiero L, Cirnaru MD, Beilina A, et al. Leucine-rich repeat kinase 2 interacts with p21-activated kinase 6 to control neurite complexity in mammalian brain. J Neurochem. 2015;135:1242–1256.
  • Kawakami F, Yabata T, Ohta E, et al. LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. Plos One. 2012;7:e30834.
  • Hamm M, Bailey R, Shaw G, et al. Physiologically relevant factors influence tau phosphorylation by leucine-rich repeat kinase 2. J Neurosci Res. 2015;93:1567–1580.
  • Shanley MR, Hawley D, Leung S, et al. LRRK2 facilitates tau phosphorylation through strong interaction with tau and cdk5. Biochemistry. 2015;54:5198–5208.
  • Guerreiro PS, Gerhardt E, Lopes Da Fonseca T, et al. LRRK2 promotes tau accumulation, aggregation and release. Mol Neurobiol. 2016;53:3124–3135.
  • Krumova P, Reyniers L, Meyer M, et al. Chemical genetic approach identifies microtubule affinity-regulating kinase 1 as a leucine-rich repeat kinase 2 substrate. Faseb J. 2015;29:2980–2992.
  • Law BM, Spain VA, Leinster VH, et al. A direct interaction between leucine-rich repeat kinase 2 and specific beta-tubulin isoforms regulates tubulin acetylation. J Biol Chem. 2014;289:895–908.
  • Russo I, Berti G, Plotegher N, et al. Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-kappaB p50 signaling in cultured microglia cells. J Neuroinflammation. 2015;12:230.
  • Gardet A, Benita Y, Li C, et al. LRRK2 is involved in the IFN-gamma response and host response to pathogens. J Immunol. 2010;185:5577–5585.
  • Kuss M, Adamopoulou E, Kahle PJ. Interferon-gamma induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages. J Neurochem. 2014;129:980–987.
  • Moehle MS, Daher JP, Hull TD, et al. The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. Hum Mol Genet. 2015;24:4250–4267.
  • Dzamko N, Inesta-Vaquera F, Zhang J, et al. The kappaB kinase family phosphorylates the Parkinson’s disease kinase LRRK2 at Ser935 and Ser910 during toll-like receptor signaling. Plos One. 2012;7:e39132.
  • Gillardon F, Schmid R, Draheim H. Parkinson’s disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity. Neuroscience. 2012;208:41–48.
  • Moehle MS, Webber PJ, Tse T, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32:1602–1611.
  • Brockmann K, Apel A, Schulte C, et al. Inflammatory profile in LRRK2-associated prodromal and clinical PD. J Neuroinflammation. 2016;13:122.
  • Ramsden N, Perrin J, Ren Z, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson’s disease-related toxicity in human neurons. ACS Chem Biol. 2011;6:1021–1028.
  • Luerman GC, Nguyen C, Samaroo H, et al. Phosphoproteomic evaluation of pharmacological inhibition of leucine-rich repeat kinase 2 reveals significant off-target effects of LRRK-2-IN-1. J Neurochem. 2014;128:561–576.
  • West AB, Moore DJ, Choi C, et al. Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet. 2007;16:223–232.
  • Jankovic J. Motor fluctuations and dyskinesias in Parkinson’s disease: clinical manifestations. Mov Disord. 2005;20(Suppl 11):S11–6.
  • Muller T, Russ H. Levodopa, motor fluctuations and dyskinesia in Parkinson’s disease. Expert Opin Pharmacother. 2006;7:1715–1730.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.