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LRRK2 Promotes Tau Accumulation, Aggregation and Release

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Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson’s disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer’s disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD.

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References

  1. Paisán-Ruíz C et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600

    Article  PubMed  Google Scholar 

  2. Zimprich A et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–7

    Article  CAS  PubMed  Google Scholar 

  3. West AB et al (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 102(46):16842–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ross OA et al (2011) Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case-control study. Lancet Neurol 10(10):898–908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11(12):791–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Greggio E (2012) Role of LRRK2 kinase activity in the pathogenesis of Parkinson’s disease. Biochem Soc Trans 40(5):1058–62

    Article  CAS  PubMed  Google Scholar 

  7. Greggio E et al (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 23(2):329–41

    Article  CAS  PubMed  Google Scholar 

  8. 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):1231–3

    Article  CAS  PubMed  Google Scholar 

  9. Taymans JM, Cookson MR (2010) Mechanisms in dominant parkinsonism: the toxic triangle of LRRK2, alpha-synuclein, and tau. Bioessays 32(3):227–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Belluzzi E, Greggio E, Piccoli G (2012) Presynaptic dysfunction in Parkinson’s disease: a focus on LRRK2. Biochem Soc Trans 40(5):1111–6

    Article  CAS  PubMed  Google Scholar 

  11. Lichtenberg M, Mansilla A, Zecchini VR, Fleming A, Rubinsztein DC (2011) The Parkinson’s disease protein LRRK2 impairs proteasome substrate clearance without affecting proteasome catalytic activity. Cell Death Dis 2, e196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3(4):519–26

    Article  CAS  PubMed  Google Scholar 

  13. Schwalbe M et al (2013) Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2. Biochemistry 52(50):9068–79

    Article  CAS  PubMed  Google Scholar 

  14. Dolan PJ, Johnson GV (2010) The role of tau kinases in Alzheimer’s disease. Curr Opin Drug Discov Devel 13(5):595–603

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98(12):6923–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chesser AS, Pritchard SM, Johnson GV (2013) Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer Disease. Front Neurol 4:122

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lee MJ, Lee JH, Rubinsztein DC (2013) Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol 105:49–59

    Article  CAS  PubMed  Google Scholar 

  18. Hamano T, Gendron TF, Ko LW, Yen SH (2009) Concentration-dependent effects of proteasomal inhibition on tau processing in a cellular model of tauopathy. Int J Clin Exp Pathol 2(6):561–73

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Krüger U, Wang Y, Kumar S, Mandelkow EM (2012) Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging 33(10):2291–305

    Article  PubMed  Google Scholar 

  20. Moreau K et al (2014) PICALM modulates autophagy activity and tau accumulation. Nat Commun 22(5):4998

  21. Kawakami F 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(1), e30834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kawakami F et al (2014) Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3β. FEBS J 281(1):3–13

    Article  CAS  PubMed  Google Scholar 

  23. Bailey RM et al (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol 126(6):809–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gonçalves SA, Matos JE, Outeiro TF (2010) Zooming into protein oligomerization in neurodegeneration using BiFC. Trends Biochem Sci 35(11):643–51

    Article  PubMed  Google Scholar 

  25. Ramirez A et al (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38(10):1184–91

    Article  CAS  PubMed  Google Scholar 

  26. Saha S, Liu-Yesucevitz L, Wolozin B (2014) Regulation of autophagy by LRRK2 in Caenorhabditis elegans. Neurodegener Dis 13(2-3):110–3

    Article  CAS  PubMed  Google Scholar 

  27. Bence NF, Bennett EJ, Kopito RR (2005) Application and analysis of the GFPu family of ubiquitin-proteasome system reporters. Methods Enzymol 399:481–90

    Article  CAS  PubMed  Google Scholar 

  28. Kisselev AF, Goldberg AL (2005) Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates. Methods Enzymol 398:364–78

    Article  CAS  PubMed  Google Scholar 

  29. Tapiola T et al (2009) Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 66(3):382–9

    Article  PubMed  Google Scholar 

  30. Guerreiro PS et al (2013) LRRK2 interactions with α-synuclein in Parkinson’s disease brains and in cell models. J Mol Med (Berl) 91(4):513–22

    Article  CAS  Google Scholar 

  31. Venderova K et al (2009) Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson’s disease. Hum Mol Genet 18(22):4390–404

    Article  CAS  PubMed  Google Scholar 

  32. Nichols RJ 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(3):393–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reyniers L et al (2014) Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways. J Neurochem. doi:10.1111/jnc.12798

    PubMed  PubMed Central  Google Scholar 

  34. Melrose HL et al (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 40(3):503–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matenia D, Mandelkow EM (2009) The tau of MARK: a polarized view of the cytoskeleton. Trends Biochem Sci 34(7):332–42

    Article  CAS  PubMed  Google Scholar 

  36. Herzig MC et al (2012) High LRRK2 levels fail to induce or exacerbate neuronal alpha-synucleinopathy in mouse brain. PLoS One 7(5), e36581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gandhi PN, Wang X, Zhu X, Chen SG, Wilson-Delfosse AL (2008) The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res 86(8):1711–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Parisiadou L et al (2009) Phosphorylation of ezrin/radixin/moesin proteins by LRRK2 promotes the rearrangement of actin cytoskeleton in neuronal morphogenesis. J Neurosci 29(44):13971–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Law BM et al (2014) A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation. J Biol Chem 289(2):895–908

    Article  CAS  PubMed  Google Scholar 

  40. Gillardon F (2009) Leucine-rich repeat kinase 2 phosphorylates brain tubulin-beta isoforms and modulates microtubule stability—a point of convergence in parkinsonian neurodegeneration? J Neurochem 110(5):1514–22

    Article  CAS  PubMed  Google Scholar 

  41. Keck S, Nitsch R, Grune T, Ullrich O (2003) Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 85(1):115–22

    Article  CAS  PubMed  Google Scholar 

  42. Giasson BI et al (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300(5619):636–40

    Article  CAS  PubMed  Google Scholar 

  43. Chaunu MP et al (2013) Juvenile frontotemporal dementia with parkinsonism associated with tau mutation G389R. J Alzheimers Dis 37(4):769–76

    CAS  PubMed  Google Scholar 

  44. David DC et al (2002) Proteasomal degradation of tau protein. J Neurochem 83(1):176–85

    Article  CAS  PubMed  Google Scholar 

  45. Wang Y, Mandelkow E (2012) Degradation of tau protein by autophagy and proteasomal pathways. Biochem Soc Trans 40(4):644–52

    Article  CAS  PubMed  Google Scholar 

  46. Manzoni C 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(4):862–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105(3):1048–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kondo K, Obitsu S, Teshima R (2011) α-Synuclein aggregation and transmission are enhanced by leucine-rich repeat kinase 2 in human neuroblastoma SH-SY5Y cells. Biol Pharm Bull 34(7):1078–83

    Article  CAS  PubMed  Google Scholar 

  49. Simón D, García-García E, Royo F, Falcón-Pérez JM, Avila J (2012) Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett 586(1):47–54

    Article  PubMed  Google Scholar 

  50. Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI (2012) Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem 287(23):19440–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fraser KB et al (2013) LRRK2 secretion in exosomes is regulated by 14-3-3. Hum Mol Genet 22(24):4988–5000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Holmberg CI et al (2004) Inefficient degradation of truncated polyglutamine proteins by the proteasome. EMBO J 23(21):4307–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors would like to thank Dr. Mika Simons for the GFP-Rab6b plasmid. PSG and TLF are supported by fellowships from Fundação para Ciência e Tecnologia with the respective fellowships (SFRH/BD/61495/2009) and (SFRH/BD/74881/2010). KE, MB and TFO are supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

PSG, EG, KE, and TFO designed the research; PSG, EG, TLF, and KE performed the experiments and analysed data; KE, MB, and TFO contributed with reagents, analytic tools, and scientific input; PSG, KE, and TFO wrote the paper.

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Authors and Affiliations

  1. Instituto de Medicina Molecular, 1649-028, Lisbon, Portugal

    Patrícia Silva Guerreiro, Tomás Lopes da Fonseca & Tiago Fleming Outeiro

  2. Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany

    Patrícia Silva Guerreiro, Ellen Gerhardt, Tomás Lopes da Fonseca & Tiago Fleming Outeiro

  3. Department of Neurology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany

    Mathias Bähr & Katrin Eckermann

  4. Department of Neurodegeneration and Restorative Research, University Medical Center Goettingen, Waldweg 33, 37073, Goettingen, Germany

    Tiago Fleming Outeiro

Authors
  1. Patrícia Silva Guerreiro
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  2. Ellen Gerhardt
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Correspondence to Tiago Fleming Outeiro.

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Guerreiro, P.S., Gerhardt, E., Lopes da Fonseca, T. et al. LRRK2 Promotes Tau Accumulation, Aggregation and Release. Mol Neurobiol 53, 3124–3135 (2016). https://doi.org/10.1007/s12035-015-9209-z

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