Pathways to Parkinsonism Redux: Convergent pathobiological mechanisms in genetics of Parkinson's disease

Human Molecular Genetics

Volumn 24, Issue R1, 2015, Pages R32-R44

  Kumaran, Ravindran ^a   Cookson, Mark R ^a  

^a NATIONAL INSTITUTE ON AGING   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA SYNUCLEIN; LEUCINE RICH REPEAT KINASE 2; TAU PROTEIN; LRRK2 PROTEIN, HUMAN; MAPT PROTEIN, HUMAN; PROTEIN SERINE THREONINE KINASE; SNCA PROTEIN, HUMAN;

AUTOPHAGY; CELL ACTIVATION; CELL TRANSPORT; GENE; GENETIC ASSOCIATION; HUMAN; INNATE IMMUNITY; LYSOSOME; MICROGLIA; MICROTUBULE; NERVE CELL; NERVOUS SYSTEM INFLAMMATION; NONHUMAN; PARKINSON DISEASE; PARKINSONISM; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ANIMAL; AUTONOMIC NERVE; GENETICS; GENOME-WIDE ASSOCIATION STUDY; IMMUNOLOGY; INFLAMMATION; METABOLISM; PATHOLOGY;

ALPHA-SYNUCLEIN; ANIMALS; AUTONOMIC PATHWAYS; GENOME-WIDE ASSOCIATION STUDY; HUMANS; INFLAMMATION; LEUCINE-RICH REPEAT SERINE-THREONINE PROTEIN KINASE-2; METABOLIC NETWORKS AND PATHWAYS; PARKINSON DISEASE; PARKINSONIAN DISORDERS; PROTEIN-SERINE-THREONINE KINASES; TAU PROTEINS;

EID: 84943806397     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddv236     Document Type: Review

References (132)

1. Parkinson, J. (2002) An essay on the shaking palsy. J. Neuropsychiatry Clin. Neurosci., 14, 223-236.
2. Trinh, J. and Farrer, M. (2013) Advances in the genetics of Parkinson disease. Nat. Rev. Neurol., 9, 445-454.
3. Polymeropoulos, M.H., Higgins, J.J., Golbe, L.I., Johnson, W.G., Ide, S.E., Di Iorio, G., Sanges, G., Stenroos, E.S., Pho, L.T., Schaffer, A.A. et al. (1996) Mapping of a gene for Parkinson's disease to chromosome 4q21-q23. Science, 274, 1197-1199.
4. Polymeropoulos, M.H., Lavedan, C., Leroy, E., Ide, S.E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R. et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science, 276, 2045-2047.
5. Corti, O., Lesage, S. and Brice, A. (2011) What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol. Rev., 91, 1161-1218.
6. Farrer, M.J. (2006) Genetics of Parkinson disease: paradigm shifts and future prospects. Nat. Rev. Genet., 7, 306-318.
7. Lin, M.K. and Farrer, M.J. (2014) Genetics and genomics of Parkinson's disease. Genome Med., 6, 48.
8. Simon-Sanchez, J., Schulte, C., Bras, J.M., Sharma, M., Gibbs, J.R., Berg, D., Paisan-Ruiz, C., Lichtner, P., Scholz, S.W., Hernandez, D.G. et al. (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat. Genet., 41, 1308-1312.
9. Satake, W., Nakabayashi, Y., Mizuta, I., Hirota, Y., Ito, C., Kubo, M., Kawaguchi, T., Tsunoda, T., Watanabe, M., Takeda, A. et al. (2009) Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat. Genet., 41, 1303-1307.
10. International Parkinson Disease Genomics Consortium-Nalls, M.A., Plagnol, V., Hernandez, D.G., Sharma, M., Sheerin, U.-M., Saad, M., Simón-Sánchez, J., Schulte, C., Lesage, S. et al. (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet, 377, 641-649.
11. Spencer, C.C.A., Su, Z., Donnelly, P. and Marchini, J. (2009) Designing genome-wide association studies: sample size, power, imputation, and the choice of genotyping chip. PLoS Genet., 5, e1000477.
12. Nalls, M.A., Pankratz, N., Lill, C.M., Do, C.B., Hernandez, D.G., Saad, M., DeStefano, A.L., Kara, E., Bras, J., Sharma, M. et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six newrisk loci for Parkinson's disease. Nat. Genet., 46, 989-993.
13. Hernandez, D.G., Nalls, M.A., Moore, M., Chong, S., Dillman, A., Trabzuni, D., Gibbs, J.R., Ryten, M., Arepalli, S., Weale, M. E. et al. (2012) Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain. Neurobiol. Dis., 47, 20-28.
14. Edwards, T.L., Scott, W.K., Almonte, C., Burt, A., Powell, E.H., Beecham, G.W., Wang, L., Züchner, S., Konidari, I., Wang, G. et al. (2010) Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann. Hum. Genet., 74, 97-109.
15. Maraganore, D.M., de Andrade, M. and Elbaz, A. et al. (2006) Collaborative analysis of a-synuclein gene promoter variability and Parkinson disease. JAMA, 296, 661-670.
16. Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K.J., Wolf, B., Berg, D., Mueller, J.C. and Gasser, T. (2008) Genetic variability in the SNCA gene influences a-synuclein levels in the blood and brain. FASEB J., 22, 1327-1334.
17. Linnertz, C., Saucier, L., Ge, D., Cronin, K.D., Burke, J.R., Browndyke, J.N., Hulette, C.M., Welsh-Bohmer, K.A. and Chiba-Falek, O. (2009) Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PloS One, 4, e7480.
18. Cronin, K.D., Ge, D., Manninger, P., Linnertz, C., Rossoshek, A., Orrison, B.M., Bernard, D.J., El-Agnaf, O.M.A., Schlossmacher, M.G., Nussbaum, R.L. et al. (2009) Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human a-synuclein in transgenic mouse brain. Hum. Mol. Genet., 18, 3274-3285.
19. Farrer, M., Kachergus, J., Forno, L., Lincoln, S., Wang, D.-S., Hulihan, M., Maraganore, D., Gwinn-Hardy, K., Wszolek, Z., Dickson, D. et al. (2004) Comparison of kindreds with parkinsonismand a-synuclein genomicmultiplications. Ann. Neurol., 55, 174-179.
20. Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R. et al. (2003) Alpha-synuclein locus triplication causes Parkinson's disease. Science, 302, 841.
21. Hardy, J. (2010) Genetic Analysis of pathways to Parkinson disease. Neuron, 68, 201-206.
22. Höglinger, G.U., Melhem, N.M., Dickson, D.W., Sleiman, P.M. A., Wang, L.-S., Klei, L., Rademakers, R., de Silva, R., Litvan, I., Riley, D.E. et al. (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat. Genet., 43, 699-705.
23. Vandrovcova, J., Pittman, A.M., Malzer, E., Abou-Sleiman, P. M., Lees, A.J., Wood, N.W. and de Silva, R. (2009) Association of MAPT haplotype-tagging SNPs with sporadic Parkinson's disease. Neurobiol. Aging, 30, 1477-1482.
24. Rajput, A., Dickson, D.W., Robinson, C.A., Ross, O.A., Dächsel, J.C., Lincoln, S.J., Cobb, S.A., Rajput, M.L. and Farrer, M.J. (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology, 67, 1506-1508.
25. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., Kachergus, J., Hulihan, M., Uitti, R.J., Calne, D.B. et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron, 44, 601-607.
26. Smith, W.W., Pei, Z., Jiang, H., Dawson, V.L., Dawson, T.M. and Ross, C.A. (2006) Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat. Neurosci., 9, 1231-1233.
27. West, A.B., Moore, D.J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C.A., Dawson, V.L. and Dawson, T.M. (2005) Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl Acad. Sci. USA, 102, 16842-16847.
28. Peeraully, T. and Tan, E.K. (2012) Genetic variants in Sporadic Parkinson's disease: East vsWest. Parkinsonism Relat. Disord., 18, Supplement 1, S63-S65.
29. Kachergus, J., Mata, I.F., Hulihan, M., Taylor, J.P., Lincoln, S., Aasly, J., Gibson, J.M., Ross, O.A., Lynch, T., Wiley, J. et al. (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am. J. Hum. Genet., 76, 672-680.
30. Wu, X., Tang, K.-F., Li, Y., Xiong, Y.-Y., Shen, L., Wei, Z.-Y., Zhou, K.-J., Niu, J.-M., Han, X., Yang, L. et al. (2012) Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson's disease: A meta-analysis. Parkinsonism Relat. Disord., 18, 722-730.
31. Schapira, A.H.V. (2015) Glucocerebrosidase and Parkinson disease: Recent advances. Mol. Cell Neurosci., 66, Part A, 37-42.
32. Nalls, M.A., Duran, R. and Lopez, G. et al. (2013) Amulticenter study of glucocerebrosidase mutations in dementia with lewy bodies. JAMA Neurol., 70, 727-735.
33. Yang, N.-Y., Lee, Y.-N., Lee, H.-J., Kim, Y.S. and Lee, S.-J. (2013) Glucocerebrosidase, a new player changing the old rules in Lewy body diseases. Biol. Chem., 394, 807-818.
34. Sidransky, E. and Lopez, G. (2012) The link between the GBA gene and parkinsonism. Lancet Neurol., 11, 986-998.
35. Sidransky, E., Nalls, M.A., Aasly, J.O., Aharon-Peretz, J., Annesi, G., Barbosa, E.R., Bar-Shira, A., Berg, D., Bras, J., Brice, A. et al. (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med., 361, 1651-1661.
36. Duran, R., Mencacci, N.E., Angeli, A.V., Shoai, M., Deas, E., Houlden, H., Mehta, A., Hughes, D., Cox, T.M., Deegan, P. et al. (2013) The glucocerobrosidase E326 K variant predisposes to Parkinson's disease, but does not cause Gaucher's disease. Mov. Disord., 28, 232-236.
37. Velayati, A., DePaolo, J., Gupta, N., Choi, J.H., Moaven, N., Westbroek, W., Goker-Alpan, O., Goldin, E., Stubblefield, B. K., Kolodny, E. et al. (2011) A mutation in SCARB2 is a modifier in Gaucher disease. Hum. Mutat., 32, 1232-1238.
38. Do, C.B., Tung, J.Y., Dorfman, E., Kiefer, A.K., Drabant, E.M., Francke, U., Mountain, J.L., Goldman, S.M., Tanner, C.M., Langston, J.W. et al. (2011) Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet., 7, e1002141.
39. Reczek, D., Schwake, M., Schröder, J., Hughes, H., Blanz, J., Jin, X., Brondyk, W., Van Patten, S., Edmunds, T. and Saftig, P. (2007) LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell, 131, 770-783.
40. Lampe, J.B., Gossrau, G., Herting, B., Kempe, A., Sommer, U., Füssel, M., Weber, M., Koch, R. and Reichmann, H. (2003) HLA typing and Parkinson's disease. Eur. Neurol., 50, 64-68.
41. Hamza, T.H., Zabetian, C.P., Tenesa, A., Laederach, A., Montimurro, J., Yearout, D., Kay, D.M., Doheny, K.F., Paschall, J., Pugh, E. et al. (2010) Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat. Genet., 42, 781-785.
42. Ahmed, I., Tamouza, R., Delord, M., Krishnamoorthy, R., Tzourio, C., Mulot, C., Nacfer, M., Lambert, J.-C., Beaune, P., Laurent-Puig, P. et al. (2012) Association between Parkinson's disease and the HLA-DRB1 locus. Mov. Disord. Off. J. Mov. Disord. Soc., 27, 1104-1110.
43. Wissemann, W.T., Hill-Burns, E.M., Zabetian, C.P., Factor, S. A., Patsopoulos, N., Hoglund, B., Holcomb, C., Donahue, R. J., Thomson, G., Erlich, H. et al. (2013) Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet., 93, 984-993.
44. Hill-Burns, E.M., Factor, S.A., Zabetian, C.P., Thomson, G. and Payami, H. (2011) Evidence for more than one Parkinson's disease-associated variant within the HLA region. PLoS ONE, 6, e27109.
45. Patsopoulos, N.A., Barcellos, L.F., Hintzen, R.Q., Schaefer, C., van Duijn, C.M., Noble, J.A., Raj, T., Gourraud, P.-A., Stranger, B.E., Oksenberg, J. et al. (2013) Fine-mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet., 9, e1003926.
46. Edvardson, S., Cinnamon, Y., Ta-Shma, A., Shaag, A., Yim, Y.-I., Zenvirt, S., Jalas, C., Lesage, S., Brice, A., Taraboulos, A. et al. (2012) A Deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS ONE, 7, e36458.
47. Steinberger, D., Weber, Y., Korinthenberg, R., Deuschl, G., Benecke, R., Martinius, J. and Müller, U. (1998) High penetrance and pronounced variation in expressivity of GCH1 mutations in five families with dopa-responsive dystonia. Ann. Neurol., 43, 634-639.
48. Mencacci, N.E., Isaias, I.U., Reich, M.M., Ganos, C., Plagnol, V., Polke, J.M., Bras, J., Hersheson, J., Stamelou, M., Pittman, A. M. et al. (2014) Parkinson's disease in GTP cyclohydrolase 1 mutation carriers. Brain J. Neurol., 137, 2480-2492.
49. Guella, I., Sherman, H.E., Appel-Cresswell, S., Rajput, A., Rajput, A.H. and Farrer, M.J. (2015) Parkinsonism in GTP cyclohydrolase 1 mutation carriers. Brain, 138, e349.
50. Holmans, P., Moskvina, V., Jones, L. and Sharma, M., (ipdgc), T.I.P.D.G.C., Vedernikov, A., Buchel, F., Sadd, M., Bras, J.M., Bettella, F. et al. (2013) A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease. Hum. Mol. Genet., 22, 1039-1049.
51. Dzamko, N., Geczy, C.L. and Halliday, G.M. Inflammation is genetically implicated in Parkinson's disease. Neuroscience. doi:10.1016/j.neuroscience.2014.10.028.
52. Tansey, M.G. and Goldberg, M.S. (2010) Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis., 37, 510-518.
53. Jang, H., Boltz, D., Sturm-Ramirez, K., Shepherd, K.R., Jiao, Y., Webster, R. and Smeyne, R.J. (2009) Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration. Proc. Natl Acad. Sci., 106, 14063-14068.
54. Reale, M., Greig, N.H. and Kamal, M.A. (2009) Peripheral chemo-cytokine profiles in Alzheimer's and Parkinson's diseases. Mini Rev. Med. Chem., 9, 1229-1241.
55. Noyce, A.J., Bestwick, J.P., Silveira-Moriyama, L., Hawkes, C. H., Giovannoni, G., Lees, A.J. and Schrag, A. (2012) Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann. Neurol., 72, 893-901.
56. Block, M.L., Zecca, L. and Hong, J.-S. (2007) Microgliamediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci., 8, 57-69.
57. McGeer, P.L., Itagaki, S., Boyes, B.E. and McGeer, E.G. (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology, 38, 1285-1291.
58. Liu, M. and Bing, G. (2011) Lipopolysaccharide animal models for Parkinson's disease. Park. Dis., 2011, e327089.
59. Kurkowska-Jastrzebska, I., Wrońska, A., Kohutnicka, M., Czlonkowski, A. and Czlonkowska, A. (1999) MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson's disease. Acta Neurobiol. Exp. (Warsz.), 59, 1-8.
60. Harms, A.S., Cao, S., Rowse, A.L., Thome, A.D., Li, X., Mangieri, L.R., Cron, R.Q., Shacka, J.J., Raman, C. and Standaert, D.G. (2013) MHCII is required for a-synuclein-induced activation of microglia, CD4T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. Off. J. Soc. Neurosci., 33, 9592-9600.
61. Theodore, S., Cao, S., McLean, P.J. and Standaert, D.G. (2008) Targeted overexpression of human a-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol., 67, 1149-1158.
62. Gao, H.-M., Kotzbauer, P.T., Uryu, K., Leight, S., Trojanowski, J.Q. and Lee, V.M.-Y. (2008) Neuroinflammation and oxidation/nitration of a-synuclein linked to dopaminergic neurodegeneration. J. Neurosci., 28, 7687-7698.
63. Lee, H.-J., Patel, S. and Lee, S.-J. (2005) Intravesicular localization and exocytosis of a-synuclein and its aggregates. J. Neurosci., 25, 6016-6024.
64. Lee, H.-J., Suk, J.-E., Bae, E.-J. and Lee, S.-J. (2008) Clearance and deposition of extracellular a-synuclein aggregates in microglia. Biochem. Biophys. Res. Commun., 372, 423-428.
65. Lee, H.-J., Suk, J.-E., Bae, E.-J., Lee, J.-H., Paik, S.R. and Lee, S.-J. (2008) Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein. Int. J. Biochem. Cell Biol., 40, 1835-1849.
66. Desplats, P., Lee, H.-J., Bae, E.-J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E. and Lee, S.-J. (2009) Inclusion formation and neuronal cell death through neuron-toneuron transmission of a-synuclein. Proc. Natl Acad. Sci., 106, 13010-13015.
67. Béraud, D., Hathaway, H.A., Trecki, J., Chasovskikh, S., Johnson, D.A., Johnson, J.A., Federoff, H.J., Shimoji, M., Mhyre, T. R. and Maguire-Zeiss, K.A. (2012) Microglial activation and antioxidant responses induced by the Parkinson's disease protein a-synuclein. J. Neuroimmune Pharmacol., 8, 94-117.
68. Kim, C., Ho, D.-H., Suk, J.-E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H.-J. et al. (2013) Neuron-released oligomeric a-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun., 4, 1562.
69. Fellner, L., Irschick, R., Schanda, K., Reindl, M., Klimaschewski, L., Poewe, W., Wenning, G.K. and Stefanova, N. (2013) Toll-like receptor 4 is required for a-synuclein dependent activation of microglia and astroglia. Glia, 61, 349-360.
70. Noelker, C., Morel, L., Lescot, T., Osterloh, A., Alvarez-Fischer, D., Breloer, M., Henze, C., Depboylu, C., Skrzydelski, D., Michel, P.P. et al. (2013) Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease. Sci. Rep., 3, 1393.
71. Zhao, J., Han, X., Xue, L., Zhu, K., Liu, H. and Xie, A. (2015) Association of TLR4 gene polymorphisms with sporadic Parkinson's disease in a Han Chinese population. Neurol. Sci., doi:10.1007/s10072-015-2227-9.
72. Overmyer, M., Helisalmi, S., Soininen, H., Laakso, M., Riekkinen, P. and Alafuzoff, I. (1999) Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue. Acta Neuropathol. (Berl.), 97, 383-392.
73. Sasaki, A., Kawarabayashi, T., Murakami, T., Matsubara, E., Ikeda, M., Hagiwara, H., Westaway, D., George-Hyslop, P.S., Shoji, M. and Nakazato, Y. (2008) Microglial activation in brain lesions with tau deposits: comparison of human tauopathies and tau transgenic mice TgTauP301L. Brain Res., 1214, 159-168.
74. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T.C., Maeda, J., Suhara, T., Trojanowski, J.Q. and Lee, V.M.-Y. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron, 53, 337-351.
75. Li, Y., Liu, L., Barger, S.W. and Griffin, W.S.T. (2003) Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. Off. J. Soc. Neurosci., 23, 1605-1611.
76. Saez, T.E., Pehar, M., Vargas, M., Barbeito, L. and Maccioni, R.B. (2004) Astrocytic nitric oxide triggers tau hyperphosphorylation in hippocampal neurons. Vivo Athens Greece, 18, 275-280.
77. Zhang, D., Lin, J. and Han, J. (2010) Receptor-interacting protein (RIP) kinase family. Cell Mol. Immunol., 7, 243-249.
78. Barrett, J.C., Hansoul, S., Nicolae, D.L., Cho, J.H., Duerr, R.H., Rioux, J.D., Brant, S.R., Silverberg, M.S., Taylor, K.D., Barmada, M.M. et al. (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet., 40, 955-962.
79. Zhang, F.-R., Huang, W., Chen, S.-M., Sun, L.-D., Liu, H., Li, Y., Cui, Y., Yan, X.-X., Yang, H.-T., Yang, R.-D. et al. (2009) Genomewide association study of leprosy. N. Engl. J. Med., 361, 2609-2618.
80. Gardet, A., Benita, Y., Li, C., Sands, B.E., Ballester, I., Stevens, C., Korzenik, J.R., Rioux, J.D., Daly, M.J., Xavier, R.J. et al. (2010) LRRK2 Is involved in the IFN-? response and host response to pathogens. J. Immunol., 185, 5577-5585.
81. Moehle, M.S., Webber, P.J., Tse, T., Sukar, N., Standaert, D.G., DeSilva, T.M., Cowell, R.M. and West, A.B. (2012) LRRK2 inhibition attenuates microglial inflammatory responses. J. Neurosci., 32, 1602-1611.
82. Dzamko, N., Inesta-Vaquera, F., Zhang, J., Xie, C., Cai, H., Arthur, S., Tan, L., Choi, H., Gray, N., Cohen, P. et al. (2012) The IkappaB kinase family phosphorylates the Parkinson's disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS ONE, 7, e39132.
83. Schapansky, J., Nardozzi, J.D., Felizia, F. and LaVoie, M.J. (2014) Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy. Hum. Mol. Genet., 23, 4201-4214.
84. Mira, M.T., Alcaïs, A., Van Thuc, N., Moraes, M.O., Di Flumeri, C., Hong Thai, V., Chi Phuong, M., Thu Huong, N., Ngoc Ba, N., Xuan Khoa, P. et al. (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature, 427, 636-640.
85. Manzanillo, P.S., Ayres, J.S., Watson, R.O., Collins, A.C., Souza, G., Rae, C.S., Schneider, D.S., Nakamura, K., Shiloh, M.U. and Cox, J.S. (2013) The ubiquitin ligase Parkin mediates resistance to intracellular pathogens. Nature, 501, 512-516.
86. Tran, T.A., Nguyen, A.D., Chang, J., Goldberg, M.S., Lee, J.-K. and Tansey, M.G. (2011) Lipopolysaccharide and tumor necrosis factor regulate Parkin expression via nuclear factor-Kappa B. PLoS ONE, 6, e23660.
87. Frank-Cannon, T.C., Tran, T., Ruhn, K.A., Martinez, T.N., Hong, J., Marvin, M., Hartley, M., Treviño, I., O'Brien, D.E., Casey, B. et al. (2008) Parkin deficiency increases vulnerability to inflammation-related Nigral degeneration. J. Neurosci., 28, 10825-10834.
88. Akundi, R.S., Huang, Z., Eason, J., Pandya, J.D., Zhi, L., Cass, W.A., Sullivan, P.G. and Büeler, H. (2011) Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE, 6, e16038.
89. Kim, J., Byun, J.-W., Choi, I., Kim, B., Jeong, H.-K., Jou, I. and Joe, E. (2013) PINK1 deficiency enhances inflammatory cytokine release from acutely prepared brain slices. Exp. Neurobiol., 22, 38-44.
90. West, A.P., Shadel, G.S. and Ghosh, S. (2011) Mitochondria in innate immune responses. Nat. Rev. Immunol., 11, 389-402.
91. Sagan, L. (1967) On the origin of mitosing cells. J. Theor. Biol., 14, 225-IN6.
92. Cardon, L.R., Burge, C., Clayton, D.A. and Karlin, S. (1994) Pervasive CpG suppression in animal mitochondrial genomes. Proc. Natl Acad. Sci. USA, 91, 3799-3803.
93. West, A.P., Brodsky, I.E., Rahner, C., Woo, D.K., Erdjument-Bromage, H., Tempst, P., Walsh, M.C., Choi, Y., Shadel, G.S. and Ghosh, S. (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature, 472, 476-480.
94. Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K. and Hauser, C.J. (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature, 464, 104-107.
95. Greene, J.C., Whitworth, A.J., Kuo, I., Andrews, L.A., Feany, M. B. and Pallanck, L.J. (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci., 100, 4078-4083.
96. Palacino, J.J., Sagi, D., Goldberg, M.S., Krauss, S., Motz, C., Wacker, M., Klose, J. and Shen, J. (2004) Mitochondrial dysfunction and oxidative damage in Parkin-deficient Mice. J. Biol. Chem., 279, 18614-18622.
97. Quarona, V., Zaccarello, G., Chillemi, A., Brunetti, E., Singh, V.K., Ferrero, E., Funaro, A., Horenstein, A.L. and Malavasi, F. (2013) CD38 and CD157: a long journey from activation markers to multifunctional molecules. Cytometry B Clin. Cytom., 84B, 207-217.
98. Yan, Y., Laroui, H., Ingersoll, S.A., Ayyadurai, S., Charania, M., Yang, S., Dalmasso, G., Obertone, T.S., Nguyen, H., Sitaraman, S.V. et al. (2011) Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice. J. Immunol. Baltim. Md 1950, 187, 1496-1505.
99. Zhang, Y., Viennois, E., Xiao, B., Baker, M.T., Yang, S., Okoro, I. and Yan, Y. (2013) Knockout of Ste20-like proline/alaninerich kinase (SPAK) attenuates intestinal inflammation in mice. Am. J. Pathol., 182, 1617-1628.
100. Jeffers, M., McDonald, W.F., Chillakuru, R.A., Yang, M., Nakase, H., Deegler, L.L., Sylander, E.D., Rittman, B., Bendele, A., Sartor, R.B. et al. (2002) A novel human fibroblast growth factor treats experimental intestinal inflammation. Gastroenterology, 123, 1151-1162.
101. Xi, P., Ding, D., Zhou, J., Wang, M. and Cong, Y.-S. (2013) DDRGK1 regulates NF-?B activity by modulating I?Ba stability. PloS One, 8, e64231.
102. Shi, F., Duan, S., Cui, J., Yan, X., Li, H., Wang, Y., Chen, F., Zhang, L., Liu, J. and Xie, X. (2014) Induction of matrix metalloproteinase-3 (MMP-3) expression in the microglia by lipopolysaccharide (LPS) via upregulation of glycoprotein nonmetastatic melanoma B (GPNMB) expression. J. Mol. Neurosci. MN, 54, 234-242.
103. Jeon, T.-I. and Osborne, T.F. (2012) SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol. Metab. TEM, 23, 65-72.
104. Yamayoshi, S., Yamashita, Y., Li, J., Hanagata, N., Minowa, T., Takemura, T. and Koike, S. (2009) Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat. Med., 15, 798-801.
105. Liscovitch, N. and French, L. (2014) Differential co-expression between a-Synuclein and IFN-? signaling genes across development and in Parkinson's disease. PLoS ONE, 9, e115029.
106. Lei, P., Ayton, S., Finkelstein, D.I., Adlard, P.A., Masters, C.L. and Bush, A.I. (2010) Tau protein: Relevance to Parkinson's disease. Int. J. Biochem. Cell Biol., 42, 1775-1778.
107. Dixit, R., Ross, J.L., Goldman, Y.E. and Holzbaur, E.L.F. (2008) Differential regulation of dynein and Kinesin motor proteins by tau. Science, 319, 1086-1089.
108. Majounie, E., Cross, W., Newsway, V., Dillman, A., Vandrovcova, J., Morris, C.M., Nalls, M.A., Ferrucci, L., Owen, M.J., O'Donovan, M.C. et al. (2013) Variation in tau isoformexpression in different brain regions and disease states. Neurobiol. Aging, 34, 1922.e7-1922.e12.
109. Muntané, G., Dalfó, E., Martinez, A. and Ferrer, I. (2008) Phosphorylation of tau and a-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer's disease, and in Parkinson's disease and related a-synucleinopathies. Neuroscience, 152, 913-923.
110. Duka, T., Rusnak, M., Drolet, R.E., Duka, V., Wersinger, C., Goudreau, J.L. and Sidhu, A. (2006) Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 20, 2302-2312.
111. Duka, T., Duka, V., Joyce, J.N. and Sidhu, A. (2009) Alpha-synuclein contributes to GSK-3beta-catalyzed tau phosphorylation in Parkinson's disease models. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 23, 2820-2830.
112. Liu, C.W., Lee, G. and Jay, D.G. (1999) Tau is required for neurite outgrowth and growth cone motility of chick sensory neurons. Cell Motil. Cytoskeleton, 43, 232-242.
113. MacLeod, D., Dowman, J., Hammond, R., Leete, T., Inoue, K. and Abeliovich, A. (2006) The familial parkinsonism gene LRRK2 regulates neurite process morphology. Neuron, 52, 587-593.
114. Bailey, R.M., Covy, J.P., Melrose, H.L., Rousseau, L., Watkinson, R., Knight, J., Miles, S., Farrer, M.J., Dickson, D.W., Giasson, B.I. et al. (2013) LRRK2 phosphorylates novel tau epitopes and promotes tauopathy. Acta Neuropathol. (Berl.), 126, 809-827.
115. Melrose, H.L., Dächsel, J.C., Behrouz, B., Lincoln, S.J., Yue, M., Hinkle, K.M., Kent, C.B., Korvatska, E., Taylor, J.P., Witten, L. et al. (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis., 40, 503-517.
116. Kawakami, F., Shimada, N., Ohta, E., Kagiya, G., Kawashima, R., Maekawa, T., Maruyama, H. and Ichikawa, T. (2014) Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3ß. FEBS J., 281, 3-13.
117. Law, B.M.H., Spain, V.A., Leinster, V.H.L., Chia, R., Beilina, A., Cho, H.J., Taymans, J.-M., Urban, M.K., Sancho, R.M., Blanca Ramírez, M. et al. (2014) A direct interaction between leucine-rich repeat kinase 2 and specific ß-tubulin isoforms regulates tubulin acetylation. J. Biol. Chem., 289, 895-908.
118. Beilina, A., Rudenko, I.N., Kaganovich, A., Civiero, L., Chau, H., Kalia, S.K., Kalia, L.V., Lobbestael, E., Chia, R., Ndukwe, K. et al. (2014) Unbiased screen for interactors of leucinerich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc. Natl Acad. Sci. USA, 111, 2626-2631.
119. MacLeod, D.A., Rhinn, H., Kuwahara, T., Zolin, A., Di Paolo, G., McCabe, B.D., MacCabe, B.D., Marder, K.S., Honig, L.S., Clark, L.N. et al. (2013) RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron, 77, 425-439.
120. Alvarez-Erviti, L., Rodriguez-Oroz, M.C., Cooper, J.M., Caballero, C., Ferrer, I., Obeso, J.A. and Schapira, A.H.V. (2010) Chaperone-mediated autophagy markers in Parkinson disease brains. Arch. Neurol., 67, 1464-1472.
121. Ahmed, I., Liang, Y., Schools, S., Dawson, V.L., Dawson, T.M. and Savitt, J.M. (2012) Development and characterization of a new Parkinson's disease model resulting from impaired autophagy. J. Neurosci. Off. J. Soc. Neurosci., 32, 16503-16509.
122. Ramirez, A., Heimbach, A., Gründemann, J., Stiller, B., Hampshire, D., Cid, L.P., Goebel, I., Mubaidin, A.F., Wriekat, A.-L., Roeper, J. et al. (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet., 38, 1184-1191.
123. Dehay, B., Ramirez, A., Martinez-Vicente, M., Perier, C., Canron, M.-H., Doudnikoff, E., Vital, A., Vila, M., Klein, C. and Bezard, E. (2012) Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl Acad. Sci. USA, 109, 9611-9616.
124. Usenovic, M., Tresse, E., Mazzulli, J.R., Taylor, J.P. and Krainc, D. (2012) Deficiency of ATP13A2 leads to lysosomal dysfunction, a-synuclein accumulation, and neurotoxicity. J. Neurosci. Off. J. Soc. Neurosci., 32, 4240-4246.
125. Gitler, A.D., Chesi, A., Geddie, M.L., Strathearn, K.E., Hamamichi, S., Hill, K.J., Caldwell, K.A., Caldwell, G.A., Cooper, A. A., Rochet, J.-C. et al. (2009) Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet., 41, 308-315.
126. Ramonet, D., Podhajska, A., Stafa, K., Sonnay, S., Trancikova, A., Tsika, E., Pletnikova, O., Troncoso, J.C., Glauser, L. and Moore, D.J. (2012) PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum. Mol. Genet., 21, 1725-1743.
127. Murphy, K.E., Gysbers, A.M., Abbott, S.K., Tayebi, N., Kim, W. S., Sidransky, E., Cooper, A., Garner, B. and Halliday, G.M. (2014) Reduced glucocerebrosidase is associated with increased a-synuclein in sporadic Parkinson's disease. Brain, 137, 834-848.
128. Cullen, V., Sardi, S.P., Ng, J., Xu, Y.-H., Sun, Y., Tomlinson, J.J., Kolodziej, P., Kahn, I., Saftig, P., Woulfe, J. et al. (2011) Acid ß-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter a-synuclein processing. Ann. Neurol., 69, 940-953.
129. Mazzulli, J.R., Xu, Y.-H., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G.A., Sidransky, E., Grabowski, G.A. and Krainc, D. (2011) Gaucher disease glucocerebrosidase and a-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell, 146, 37-52.
130. Clark, I.E., Dodson, M.W., Jiang, C., Cao, J.H., Huh, J.R., Seol, J. H., Yoo, S.J., Hay, B.A. and Guo, M. (2006) Drosophila pink1 is required for mitochondrial function and interacts genetically with Parkin. Nature, 441, 1162-1166.
131. McCarthy, M.I., Abecasis, G.R., Cardon, L.R., Goldstein, D.B., Little, J., Ioannidis, J.P.A. and Hirschhorn, J.N. (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet., 9, 356-369.
132. Kalia, L.V. and Lang, A.E. (2015) Parkinson's disease. Lancet, doi:10.1016/S0140-6736(14)61393-3.