Cellular and molecular basis of neurodegeneration in Parkinson disease

Frontiers in Aging Neuroscience

Volumn 10, Issue APR, 2018, Pages

  Zeng, Xian Si ^a   Geng, Wen Shuo ^a   Jia, Jin Jing ^a   Chen, Lei ^a   Zhang, Peng Peng ^a  

^a XINYANG NORMAL UNIVERSITY   (China)

Author keywords

Gene mutation; Mechanism; Neurodegeneration; Neuronal death; Parkinson disease

Indexed keywords

ALPHA SYNUCLEIN; DOPAMINE; GLUCOSYLCERAMIDASE; GLUCOSYLCERAMIDASE 1; LEUCINE RICH REPEAT KINASE 2; MEMBRANE PROTEIN; PARKIN; PROTEIN DEGLYCASE DJ-1; PROTEIN KINASE; PTEN INDUCED PUTATIVE KINASE 1; UNCLASSIFIED DRUG; VACUOLAR PROTEIN SORTING 35;

ALPHA SYNUCLEIN GENE; AUTOPHAGY; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DJ 1 GENE; DOPAMINE METABOLISM; DOPAMINERGIC NERVE CELL; ENDOPLASMIC RETICULUM STRESS; GBA1 GENE; GENE MUTATION; GENETIC ASSOCIATION; HUMAN; IMMUNOREGULATION; LRRK2 GENE; MUTATIONAL ANALYSIS; NERVE CELL NECROSIS; NERVE DEGENERATION; NEUROPATHOLOGY; NONHUMAN; PARKIN GENE; PARKINSON DISEASE; PINK1 GENE; REVIEW; VPS35 GENE;

EID: 85045747283     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2018.00109     Document Type: Review

References (203)

1. Ablat, N., Lv, D., Ren, R., Xiaokaiti, Y., Ma, X., Zhao, X., et al. (2016). Neuroprotective effects of a standardized flavonoid extract from safflower against a rotenone-induced rat model of Parkinson's disease. Molecules 21:E1107. doi: 10.3390/molecules21091107
2. Akiyama, H., and McGeer, P. L. (1989). Microglial response to 6-hydroxydopamine-induced substantia nigra lesions. Brain Res. 489, 247-253. doi: 10.1016/0006-8993(89)90857-3
3. Alarcon-Aris, D., Recasens, A., Galofre, M., Carballo-Carbajal, I., Zacchi, N., Ruiz-Bronchal, E., et al. (2017). Selective alpha-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson's disease. Mol. Ther. 26, 550-567. doi: 10.1016/j.ymthe.2017.11.015
4. Ando, M., Fiesel, F. C., Hudec, R., Caulfield, T. R., Ogaki, K., Gorka-Skoczylas, P., et al. (2017). The PINK1 p. I368N mutation affects protein stability and ubiquitin kinase activity. Mol. Neurodegener. 12:32. doi: 10.1186/s13024-017-0174-z
5. Bae, E. J., Yang, N. Y., Lee, C., Lee, H. J., Kim, S., Sardi, S. P., et al. (2015). Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation. Exp. Mol. Med. 47:e153. doi: 10.1038/emm.2014.128
6. Bai, J., Nakamura, H., Kwon, Y. W., Tanito, M., Ueda, S., Tanaka, T., et al. (2007). Does thioredoxin-1 prevent mitochondria-and endoplasmic reticulum-mediated neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine? Antioxid. Redox Signal. 9, 603-608. doi: 10.1089/ars.2006.1513
7. Balestrino, R., and Schapira, A. H. V. (2018). Glucocerebrosidase and Parkinson disease: molecular, clinical, and therapeutic implications. Neuroscientist doi: 10.1177/1073858417748875 [Epub ahead of print]
8. Bandres-Ciga, S., and Cookson, M. R. (2017). Alpha-synuclein triggers T-cell response. Is Parkinson's disease an autoimmune disorder?. Mov. Disord. 32:1327. doi: 10.1002/mds.27116
9. Batelli, S., Invernizzi, R. W., Negro, A., Calcagno, E., Rodilossi, S., Forloni, G., et al. (2015). The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity. Neurodegener. Dis. 15, 13-23. doi: 10.1159/000367993
10. Bekris, L. M., Mata, I. F., and Zabetian, C. P. (2010). The genetics of Parkinson disease. J. Geriatr. Psychiatry Neurol. 23, 228-242. doi: 10.1177/0891988710383572
11. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., and Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301-1306. doi: 10.1038/81834
12. Bido, S., Soria, F. N., Fan, R. Z., Bezard, E., and Tieu, K. (2017). Mitochondrial division inhibitor-1 is neuroprotective in the A53T-alpha-synuclein rat model of Parkinson's disease. Sci. Rep. 7:7495. doi: 10.1038/s41598-017-07181-0
13. Biosa, A., Sandrelli, F., Beltramini, M., Greggio, E., Bubacco, L., and Bisaglia, M. (2017). Recent findings on the physiological function of DJ-1: beyond Parkinson's disease. Neurobiol. Dis. 108, 65-72. doi: 10.1016/j.nbd.2017.08.005
14. Blum-Degen, D., Muller, T., Kuhn, W., Gerlach, M., Przuntek, H., and Riederer, P. (1995). Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci. Lett. 202, 17-20. doi: 10.1016/0304-3940(95)12192-7
15. Bonifacino, J. S., and Hurley, J. H. (2008). Retromer. Curr. Opin. Cell Biol. 20, 427-436. doi: 10.1016/j.ceb.2008.03.009
16. Bonifati, V., Rizzu, P., Squitieri, F., Krieger, E., Vanacore, N., van Swieten, J. C., et al. (2003). DJ-1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurol. Sci. 24, 159-160. doi: 10.1007/s10072-003-0108-0
17. Brito-Armas, J. M., Baekelandt, V., Castro-Hernandez, J. R., Gonzalez-Hernandez, T., Rodriguez, M., and Castro, R. (2013). Melatonin prevents dopaminergic cell loss induced by lentiviral vectors expressing A30P mutant alpha-synuclein. Histol. Histopathol. 28, 999-1006. doi: 10.14670/HH-28.999
18. Brodacki, B., Staszewski, J., Toczylowska, B., Kozlowska, E., Drela, N., Chalimoniuk, M., et al. (2008). Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci. Lett. 441, 158-162. doi: 10.1016/j.neulet.2008.06.040
19. Burbulla, L. F., Song, P., Mazzulli, J. R., Zampese, E., Wong, Y. C., Jeon, S., et al. (2017). Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357, 1255-1261. doi: 10.1126/science.aam9080
20. Cai, Y., Arikkath, J., Yang, L., Guo, M. L., Periyasamy, P., and Buch, S. (2016). Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. Autophagy 12, 225-244. doi: 10.1080/15548627.2015.1121360
21. Cannon, J. R., Geghman, K. D., Tapias, V., Sew, T., Dail, M. K., Li, C., et al. (2013). Expression of human E46K-mutated alpha-synuclein in BAC-transgenic rats replicates early-stage Parkinson's disease features and enhances vulnerability to mitochondrial impairment. Exp. Neurol. 240, 44-56. doi: 10.1016/j.expneurol.2012.11.007
22. Cebrian, C., Zucca, F. A., Mauri, P., Steinbeck, J. A., Studer, L., Scherzer, C. R., et al. (2014). MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat. Commun. 5:3633. doi: 10.1038/ncomms4633
23. Celardo, I., Costa, A. C., Lehmann, S., Jones, C., Wood, N., Mencacci, N. E., et al. (2016). Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease. Cell Death Dis. 23:e2271. doi: 10.1038/cddis.2016.173
24. Chen, Y. F., Chang, Y. Y., Lan, M. Y., Chen, P. L., and Lin, C. H. (2017). Identification of VPS35 p. D620N mutation-related Parkinson's disease in a Taiwanese family with successful bilateral subthalamic nucleus deep brain stimulation: a case report and literature review. BMC Neurol. 17:191. doi: 10.1186/s12883-017-0972-5
25. Choi, W. S., Palmiter, R. D., and Xia, Z. (2011). Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson's disease model. J. Cell Biol. 192, 873-882. doi: 10.1083/jcb.201009132
26. Chung, C. Y., Koprich, J. B., Siddiqi, H., and Isacson, O. (2009). Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV alpha-synucleinopathy. J. Neurosci. 29, 3365-3373. doi: 10.1523/JNEUROSCI.5427-08.2009
27. Cleeter, M. W., Chau, K. Y., Gluck, C., Mehta, A., Hughes, D. A., Duchen, M., et al. (2013). Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. Neurochem. Int. 62, 1-7. doi: 10.1016/j.neuint.2012.10.010
28. Colla, E., Coune, P., Liu, Y., Pletnikova, O., Troncoso, J. C., Iwatsubo, T., et al. (2012). Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J. Neurosci. 32, 3306-3320. doi: 10.1523/JNEUROSCI.5367-11.2012
29. Connolly, N. M. C., Theurey, P., Adam-Vizi, V., Bazan, N. G., Bernardi, P., Bolanos, J. P., et al. (2017). Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ. 25, 542-572. doi: 10.1038/s41418-017-0020-4
30. Cooper, J. F., Machiela, E., Dues, D. J., Spielbauer, K. K., Senchuk, M. M., and Van Raamsdonk, J. M. (2017). Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models. Sci. Rep. 7:16441. doi: 10.1038/s41598-017-16637-2
31. Cooper, J. M., Wiklander, P. B., Nordin, J. Z., Al-Shawi, R., Wood, M. J., Vithlani, M., et al. (2014). Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Mov. Disord. 29, 1476-1485. doi: 10.1002/mds.25978
32. Coppola-Segovia, V., Cavarsan, C., Maia, F. G., Ferraz, A. C., Nakao, L. S., Lima, M. M., et al. (2017). ER stress induced by tunicamycin triggers alpha-synuclein oligomerization, dopaminergic neurons death and locomotor impairment: a new model of Parkinson's disease. Mol. Neurobiol. 54, 5798-5806. doi: 10.1007/s12035-016-0114-x
33. Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., and Sulzer, D. (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 1292-1295. doi: 10.1126/science.1101738
34. Dabbeni-Sala, F., Di Santo, S., Franceschini, D., Skaper, S. D., and Giusti, P. (2001). Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J. 15, 164-170. doi: 10.1096/fj.00-0129com
35. Deeg, S., Gralle, M., Sroka, K., Bahr, M., Wouters, F. S., and Kermer, P. (2010). BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity. J. Cell Biol. 188, 505-513. doi: 10.1083/jcb.200904103
36. Dirkx, M. F., den Ouden, H. E., Aarts, E., Timmer, M. H., Bloem, B. R., Toni, I., et al. (2017). Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus. Brain 140, 721-734. doi: 10.1093/brain/aww331
37. Ejlerskov, P., Hultberg, J. G., Wang, J., Carlsson, R., Ambjorn, M., Kuss, M., et al. (2015). Lack of neuronal IFN-beta-IFNAR causes lewy body-and Parkinson's disease-like dementia. Cell. 163, 324-339. doi: 10.1016/j.cell.2015.08.069
38. Fang, F., Yang, W., Florio, J. B., Rockenstein, E., Spencer, B., Orain, X. M., et al. (2017). Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease. Sci. Rep. 7:3868. doi: 10.1038/s41598-017-04232-4
39. Farrer, M., Kachergus, J., Forno, L., Lincoln, S., Wang, D. S., Hulihan, M., et al. (2004). Comparison of kindreds with parkinsonism and alpha-synuclein genomic multiplications. Ann. Neurol. 55, 174-179. doi: 10.1002/ana.10846
40. Feng, C. W., Hung, H. C., Huang, S. Y., Chen, C. H., Chen, Y. R., Chen, C. Y., et al. (2016). Neuroprotective effect of the marine-derived compound 11-Dehydrosinulariolide through DJ-1-related pathway in in vitro and in vivo models of Parkinson's disease. Mar. Drugs 14:E187. doi: 10.3390/md14100187
41. Ferreira, M., and Massano, J. (2017). An updated review of Parkinson's disease genetics and clinicopathological correlations. Acta Neurol. Scand. 135, 273-284. doi: 10.1111/ane.12616
42. Follett, J., Bugarcic, A., Yang, Z., Ariotti, N., Norwood, S. J., Collins, B. M., et al. (2016). Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces α-synuclein aggregation. J. Biol. Chem. 291, 18283-18298. doi: 10.1074/jbc. M115.703157
43. Fouillet, A., Levet, C., Virgone, A., Robin, M., Dourlen, P., Rieusset, J., et al. (2012). ER stress inhibits neuronal death by promoting autophagy. Autophagy 8, 915-926. doi: 10.4161/auto.19716
44. Gandhi, S., Vaarmann, A., Yao, Z., Duchen, M. R., Wood, N. W., and Abramov, A. Y. (2012). Dopamine induced neurodegeneration in a PINK1 model of Parkinson's disease. PLoS One 7:e37564. doi: 10.1371/journal.pone.0037564
45. Gan-Or, Z., Dion, P. A., and Rouleau, G. A. (2015). Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease. Autophagy 11, 1443-1457. doi: 10.1080/15548627.2015.1067364
46. Gao, F., Yang, J., Wang, D., Li, C., Fu, Y., Wang, H., et al. (2017). Mitophagy in Parkinson's disease: pathogenic and therapeutic implications. Front. Neurol. 8:527. doi: 10.3389/fneur.2017.00527
47. Garcia-Sanz, P., Orgaz, L., Bueno-Gil, G., Espadas, I., Rodriguez-Traver, E., Kulisevsky, J., et al. (2017). N370S-GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson's disease. Mov. Disord. 32, 1409-1422. doi: 10.1002/mds.27119
48. Garcia-Sanz, P., Orgaz, L., Fuentes, J. M., Vicario, C., and Moratalla, R. (2018). Cholesterol and multilamellar bodies: lyosomal dysfunction in GBA-Parkinson disease. Autophagy 25, 1-7. doi: 10.1080/15548627.2018.1427396
49. Giaime, E., Sunyach, C., Druon, C., Scarzello, S., Robert, G., Grosso, S., et al. (2010). Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6. Cell Death Differ. 17, 158-169. doi: 10.1038/cdd.2009.116
50. Goldstein, D. S., Kopin, I. J., and Sharabi, Y. (2014). Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders. Pharmacol. Ther. 144, 268-282. doi: 10.1016/j.pharmthera.2014.06.006
51. Goldstein, D. S., Sullivan, P., Cooney, A., Jinsmaa, Y., Sullivan, R., Gross, D. J., et al. (2012). Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease. J. Neurochem. 123, 932-943. doi: 10.1111/j.1471-4159.2012.07924.x
52. Gorbatyuk, M. S., Shabashvili, A., Chen, W., Meyers, C., Sullivan, L. F., Salganik, M., et al. (2012). Glucose regulated protein 78 diminishes alpha-synuclein neurotoxicity in a rat model of Parkinson disease. Mol. Ther. 20, 1327-1337. doi: 10.1038/mt.2012.28
53. Grunewald, A., Rygiel, K. A., Hepplewhite, P. D., Morris, C. M., Picard, M., and Turnbull, D. M. (2016). Mitochondrial DNA depletion in respiratory chain-deficient Parkinson disease neurons. Ann. Neurol. 79, 366-378. doi: 10.1002/ana.24571
54. Gully, J. C., Sergeyev, V. G., Bhootada, Y., Mendez-Gomez, H., Meyers, C. A., Zolotukhin, S., et al. (2016). Up-regulation of activating transcription factor 4 induces severe loss of dopamine nigral neurons in a rat model of Parkinson's disease. Neurosci. Lett. 627, 36-41. doi: 10.1016/j.neulet.2016.05.039
55. Han, K. A., Shin, W. H., Jung, S., Seol, W., Seo, H., Ko, C., et al. (2017). Leucine-rich repeat kinase 2 exacerbates neuronal cytotoxicity through phosphorylation of histone deacetylase 3 and histone deacetylation. Hum. Mol. Genet. 26, 1-18. doi: 10.1093/hmg/ddw363
56. Haque, M. E., Mount, M. P., Safarpour, F., Abdel-Messih, E., Callaghan, S., Mazerolle, C., et al. (2012). Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J. Biol. Chem. 287, 23162-23170. doi: 10.1074/jbc. M112.346437
57. Harms, A. S., Thome, A. D., Yan, Z., Schonhoff, A. M., Williams, G. P., Li, X., et al. (2018). Peripheral monocyte entry is required for alpha-Synuclein induced inflammation and Neurodegeneration in a model of Parkinson disease. Exp. Neurol. 300, 179-187. doi: 10.1016/j.expneurol.2017.11.010
58. Healy, D. G., Falchi, M., O'Sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., et al. (2008). Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583-590. doi: 10.1016/S1474-4422(08)70117-0
59. Heman-Ackah, S. M., Manzano, R., Hoozemans, J. J. M., Scheper, W., Flynn, R., Haerty, W., et al. (2017). Alpha-synuclein induces the unfolded protein response in Parkinson's disease SNCA triplication iPSC-derived neurons. Hum. Mol. Genet. 26, 4441-4450. doi: 10.1093/hmg/ddx331
60. Herrera, A., Munoz, P., Steinbusch, H. W. M., and Segura-Aguilar, J. (2017). Are dopamine oxidation metabolites involved in the loss of dopaminergic neurons in the nigrostriatal system in Parkinson's disease? ACS Chem. Neurosci. 8, 702-711. doi: 10.1021/acschemneuro.7b00034
61. Ho, D. H., Jang, J., Joe, E. H., Son, I., Seo, H., and Seol, W. (2016). G2385R and I2020T mutations increase LRRK2 GTPase activity. Biomed. Res. Int. 2016:7917128. doi: 10.1155/2016/7917128
62. Howlett, E. H., Jensen, N., Belmonte, F., Zafar, F., Hu, X., Kluss, J., et al. (2017). LRRK2 G2019S-induced mitochondrial DNA damage is LRRK2 kinase dependent and inhibition restores mtDNA integrity in Parkinson's disease. Hum. Mol. Genet. 26, 4340-4351. doi: 10.1093/hmg/ddx320
63. Hu, Z. Y., Chen, B., Zhang, J. P., and Ma, Y. Y. (2017). Up-regulation of autophagy-related gene 5 (ATG5) protects dopaminergic neurons in a zebrafish model of Parkinson's disease. J. Biol. Chem. 292, 18062-18074. doi: 10.1074/jbc. M116.764795
64. Huang, E., Qu, D., Huang, T., Rizzi, N., Boonying, W., Krolak, D., et al. (2017). PINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress. Nat. Commun. 8:1399. doi: 10.1038/s41467-017-01435-1
65. Ibanez, L., Dube, U., Saef, B., Budde, J., Black, K., Medvedeva, A., et al. (2017). Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels. BMC Neurol. 17:198. doi: 10.1186/s12883-017-0978-z
66. Im, J. Y., Lee, K. W., Woo, J. M., Junn, E., and Mouradian, M. M. (2012). DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum. Mol. Genet. 21, 3013-3024. doi: 10.1093/hmg/dds131
67. Ishikawa, S., Taira, T., Niki, T., Takahashi-Niki, K., Maita, C., Maita, H., et al. (2009). Oxidative status of DJ-1-dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-dihydroxy-L-phenylalanine (L-DOPA) decarboxylase with DJ-1. J. Biol. Chem. 284, 28832-28844. doi: 10.1074/jbc. M109.019950
68. Jiang, M., Porat-Shliom, Y., Pei, Z., Cheng, Y., Xiang, L., Sommers, K., et al. (2010). Baicalein reduces E46K alpha-synuclein aggregation in vitro and protects cells against E46K alpha-synuclein toxicity in cell models of familiar Parkinsonism. J. Neurochem. 114, 419-429. doi: 10.1111/j.1471-4159.2010.06752.x
69. Jimenez-Ferrer, I., Jewett, M., Tontanahal, A., Romero-Ramos, M., and Swanberg, M. (2017). Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to alpha-synuclein-induced dopaminergic neurodegeneration. Neurobiol. Dis. 106, 279-290. doi: 10.1016/j.nbd.2017.07.016
70. Jing, X., Shi, Q., Bi, W., Zeng, Z., Liang, Y., Wu, X., et al. (2014). Rifampicin protects PC12 cells from rotenone-induced cytotoxicity by activating GRP78 via PERK-eIF2alpha-ATF4 pathway. PLoS One 9:e92110. doi: 10.1371/journal.pone.0092110
71. Ju, C., Gao, J., Hou, L., Wang, L., Zhang, F., Sun, F., et al. (2017). Neuroprotective effect of chondroitin sulfate on SHSY5Y cells overexpressing wild-type or A53T mutant alphasynuclein. Mol. Med. Rep. 16, 8721-8728. doi: 10.3892/mmr.2017.7725
72. Kang, S. S., Zhang, Z., Liu, X., Manfredsson, F. P., Benskey, M. J., Cao, X., et al. (2017). TrkB neurotrophic activities are blocked by alpha-synuclein, triggering dopaminergic cell death in Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 114, 10773-10778. doi: 10.1073/pnas.1713969114
73. Karampetsou, M., Ardah, M. T., Semitekolou, M., Polissidis, A., Samiotaki, M., Kalomoiri, M., et al. (2017). Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice. Sci. Rep. 7:16533. doi: 10.1038/s41598-017-15813-8
74. Karuppagounder, S. S., Xiong, Y., Lee, Y., Lawless, M. C., Kim, D., Nordquist, E., et al. (2016). LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. J. Chem. Neuroanat. 76, 90-97. doi: 10.1016/j.jchemneu.2016.01.007
75. Kaufman, R. J. (2002). Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 110, 1389-1398. doi: 10.1172/JCI0216886
76. Khaldy, H., Escames, G., Leon, J., Bikjdaouene, L., and Acuna-Castroviejo, D. (2003). Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion. Neurobiol. Aging 24, 491-500. doi: 10.1016/S0197-4580(02)00133-1
77. Kikuchi, T., Morizane, A., Doi, D., Magotani, H., Onoe, H., Hayashi, T., et al. (2017). Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model. Nature 548, 592-596. doi: 10.1038/nature23664
78. Kilpatrick, B. S., Magalhaes, J., Beavan, M. S., McNeill, A., Gegg, M. E., Cleeter, M. W., et al. (2016). Endoplasmic reticulum and lysosomal Ca(2)(+) stores are remodelled in GBA1-linked Parkinson disease patient fibroblasts. Cell Calcium 59, 12-20. doi: 10.1016/j.ceca.2015.11.002
79. Kim, B., Yang, M. S., Choi, D., Kim, J. H., Kim, H. S., Seol, W., et al. (2012). Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. PLoS One 7:e34693. doi: 10.1371/journal.pone.0034693
80. Kim, S., Yun, S. P., Lee, S., Umanah, G. E., Bandaru, V. V. R., Yin, X., et al. (2018). GBA1 deficiency negatively affects physiological alpha-synuclein tetramers and related multimers. Proc. Natl. Acad. Sci. U.S.A. 115, 798-803. doi: 10.1073/pnas.1700465115
81. Klein, R. L., King, M. A., Hamby, M. E., and Meyer, E. M. (2002). Dopaminergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13, 605-612. doi: 10.1089/10430340252837206
82. Kumar, A., Tamjar, J., Waddell, A. D., Woodroof, H. I., Raimi, O. G., Shaw, A. M., et al. (2017). Structure of PINK1 and mechanisms of Parkinson's disease-associated mutations. Elife 6:e29985. doi: 10.7554/eLife.29985
83. Langston, J. W., Ballard, P., Tetrud, J. W., and Irwin, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979-980. doi: 10.1126/science.6823561
84. Lee, S., Oh, S. T., Jeong, H. J., Pak, S. C., Park, H. J., Kim, J., et al. (2017). MPTP-induced vulnerability of dopamine neurons in A53T alpha-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation. Korean J. Physiol. Pharmacol. 21, 625-632. doi: 10.4196/kjpp.2017.21.6.625
85. Lewis, J., Melrose, H., Bumcrot, D., Hope, A., Zehr, C., Lincoln, S., et al. (2008). In vivo silencing of alpha-synuclein using naked siRNA. Mol. Neurodegener. 3:19. doi: 10.1186/1750-1326-3-19
86. Li, W., Zhu, J., Dou, J., She, H., Tao, K., Xu, H., et al. (2017). Phosphorylation of LAMP2A by p38 MAPK couples ER stress to chaperone-mediated autophagy. Nat. Commun. 8:1763. doi: 10.1038/s41467-017-01609-x
87. Lieberman, O. J., Choi, S. J., Kanter, E., Saverchenko, A., Frier, M. D., Fiore, G. M., et al. (2017). alpha-synuclein-dependent calcium entry underlies differential sensitivity of cultured SN and VTA dopaminergic neurons to a Parkinsonian neurotoxin. eNeuro 4:ENEURO.0167-17.2017. doi: 10.1523/ENEURO.0167-17.2017
88. Liu, J., Wang, X., Lu, Y., Duan, C., Gao, G., Lu, L., et al. (2017). Pink1 interacts with alpha-synuclein and abrogates alpha-synuclein-induced neurotoxicity by activating autophagy. Cell Death Dis. 8:e3056. doi: 10.1038/cddis.2017.427
89. Liu, S., Cui, B., Dai, Z. X., Shi, P. K., Wang, Z. H., and Guo, Y. Y. (2016). Long Non-coding RNA HOTAIR promotes Parkinson's disease induced by MPTP through up-regulating the expression of LRRK2. Curr. Neurovasc. Res. 13, 115-120. doi: 10.2174/1567202613666160316155228
90. Liu, Z., Yu, Y., Li, X., Ross, C. A., and Smith, W. W. (2011). Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol. Res. 63, 439-444. doi: 10.1016/j.phrs.2011.01.004
91. Luth, E. S., Stavrovskaya, I. G., Bartels, T., Kristal, B. S., and Selkoe, D. J. (2014). Soluble, prefibrillar alpha-synuclein oligomers promote complex I-dependent, Ca2+-induced mitochondrial dysfunction. J. Biol. Chem. 289, 21490-21507. doi: 10.1074/jbc. M113.545749
92. Lutz, A. K., Exner, N., Fett, M. E., Schlehe, J. S., Kloos, K., Lammermann, K., et al. (2009). Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J. Biol. Chem. 284, 22938-22951. doi: 10.1074/jbc. M109.035774
93. Magalhaes, J., Gegg, M. E., Migdalska-Richards, A., Doherty, M. K., Whitfield, P. D., and Schapira, A. H. (2016). Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease. Hum. Mol. Genet. 25, 3432-3445. doi: 10.1093/hmg/ddw185
94. Mao, X., Ou, M. T., Karuppagounder, S. S., Kam, T. I., Yin, X., Xiong, Y., et al. (2016). Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353:aah3374. doi: 10.1126/science.aah3374
95. Martinat, C., Shendelman, S., Jonason, A., Leete, T., Beal, M. F., Yang, L., et al. (2004). Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-derived cell model of primary Parkinsonism. PLoS Biol. 2:e327. doi: 10.1371/journal.pbio.0020327
96. Martinez, B. A., Petersen, D. A., Gaeta, A. L., Stanley, S. P., Caldwell, G. A., and Caldwell, K. A. (2017). Dysregulation of the mitochondrial unfolded protein response induces non-apoptotic dopaminergic neurodegeneration in C. elegans Models of Parkinson's Disease. J. Neurosci. 37, 11085-11100. doi: 10.1523/JNEUROSCI.1294-17.2017
97. Mason, R. J., Paskins, A. R., Dalton, C. F., and Smith, D. P. (2016). Copper binding and subsequent aggregation of alpha-synuclein are modulated by N-terminal acetylation and ablated by the H50Q missense mutation. Biochemistry 55, 4737-4741. doi: 10.1021/acs.biochem.6b00708
98. Matheoud, D., Sugiura, A., Bellemare-Pelletier, A., Laplante, A., Rondeau, C., Chemali, M., et al. (2016). Parkinson's disease-related proteins PINK1 and parkin repress mitochondrial antigen presentation. Cell 166, 314-327. doi: 10.1016/j.cell.2016.05.039
99. Matsumoto, J., Stewart, T., Sheng, L., Li, N., Bullock, K., Song, N., et al. (2017). Transmission of alpha-synuclein-containing erythrocyte-derived extracellular vesicles across the blood-brain barrier via adsorptive mediated transcytosis: another mechanism for initiation and progression of Parkinson's disease? Acta Neuropathol. Commun. 5:71. doi: 10.1186/s40478-017-0470-4
100. Mazzulli, J. R., Zunke, F., Tsunemi, T., Toker, N. J., Jeon, S., Burbulla, L. F., et al. (2016). Activation of beta-glucocerebrosidase reduces pathological alpha-synuclein and restores lysosomal function in Parkinson's patient midbrain neurons. J. Neurosci. 36, 7693-7706. doi: 10.1523/JNEUROSCI.0628-16.2016
101. Mbefo, M. K., Fares, M. B., Paleologou, K., Oueslati, A., Yin, G., Tenreiro, S., et al. (2015). Parkinson disease mutant E46K enhances alpha-synuclein phosphorylation in mammalian cell lines, in yeast, and in vivo. J. Biol. Chem. 290, 9412-9427. doi: 10.1074/jbc. M114.610774
102. McGeer, P. L., Schwab, C., Parent, A., and Doudet, D. (2003). Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Ann. Neurol. 54, 599-604. doi: 10.1002/ana.10728
103. McNeill, A., Duran, R., Hughes, D. A., Mehta, A., and Schapira, A. H. (2012). A clinical and family history study of Parkinson's disease in heterozygous glucocerebrosidase mutation carriers. J. Neurol. Neurosurg. Psychiatry 83, 853-854. doi: 10.1136/jnnp-2012-302402
104. Meiser, J., Delcambre, S., Wegner, A., Jager, C., Ghelfi, J., d'Herouel, A. F., et al. (2016). Loss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism. Neurobiol. Dis. 89, 112-125. doi: 10.1016/j.nbd.2016.01.019
105. Migdalska-Richards, A., Daly, L., Bezard, E., and Schapira, A. H. (2016). Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice. Ann. Neurol. 80, 766-775. doi: 10.1002/ana.24790
106. Migdalska-Richards, A., Wegrzynowicz, M., Rusconi, R., Deangeli, G., Di Monte, D. A., Spillantini, M. G., et al. (2017). The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice. Brain 140, 2706-2721. doi: 10.1093/brain/awx221
107. Minakaki, G., Menges, S., Kittel, A., Emmanouilidou, E., Schaeffner, I., Barkovits, K., et al. (2017). Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype. Autophagy 14, 98-119. doi: 10.1080/15548627.2017.1395992
108. Mittal, S., Bjornevik, K., Im, D. S., Flierl, A., Dong, X., Locascio, J. J., et al. (2017). beta2-Adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson's disease. Science 357, 891-898. doi: 10.1126/science.aaf3934
109. Mogi, M., Harada, M., Kondo, T., Riederer, P., Inagaki, H., Minami, M., et al. (1994a). Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from parkinsonian patients. Neurosci. Lett. 180, 147-150
110. Mogi, M., Harada, M., Riederer, P., Narabayashi, H., Fujita, K., and Nagatsu, T. (1994b). Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neurosci. Lett. 165, 208-210. doi: 10.1016/0304-3940(94)90746-3
111. Mor, D. E., Tsika, E., Mazzulli, J. R., Gould, N. S., Kim, H., Daniels, M. J., et al. (2017). Dopamine induces soluble alpha-synuclein oligomers and nigrostriatal degeneration. Nat. Neurosci. 20, 1560-1568. doi: 10.1038/nn.4641
112. Mortiboys, H., Aasly, J., and Bandmann, O. (2013). Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease. Brain 136, 3038-3050. doi: 10.1093/brain/awt224
113. Mortiboys, H., Furmston, R., Bronstad, G., Aasly, J., Elliott, C., and Bandmann, O. (2015). UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology 85, 846-852. doi: 10.1212/WNL.0000000000001905
114. Mosharov, E. V., Larsen, K. E., Kanter, E., Phillips, K. A., Wilson, K., Schmitz, Y., et al. (2009). Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 62, 218-229. doi: 10.1016/j.neuron.2009.01.033
115. Mukherjee, U. A., Ong, S. B., Ong, S. G., and Hausenloy, D. J. (2015). Parkinson's disease proteins: novel mitochondrial targets for cardioprotection. Pharmacol. Ther. 156, 34-43. doi: 10.1016/j.pharmthera.2015.10.005
116. Murphy, K. E., Gysbers, A. M., Abbott, S. K., Tayebi, N., Kim, W. S., Sidransky, E., et al. (2014). Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. Brain 137, 834-848. doi: 10.1093/brain/awt367
117. Mutez, E., Nkiliza, A., Belarbi, K., de Broucker, A., Vanbesien-Mailliot, C., Bleuse, S., et al. (2014). Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease. Neurobiol. Dis. 63, 165-170. doi: 10.1016/j.nbd.2013.11.007
118. Narendra, D., Tanaka, A., Suen, D. F., and Youle, R. J. (2009). Parkin-induced mitophagy in the pathogenesis of Parkinson disease. Autophagy 5, 706-708. doi: 10.4161/auto.5.5.8505
119. Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D. F., Gautier, C. A., Shen, J., et al. (2010). PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8:e1000298. doi: 10.1371/journal.pbio.1000298
120. Nguyen, A. P. T., Daniel, G., Valdes, P., Islam, M. S., Schneider, B. L., and Moore, D. J. (2018). G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain. Hum. Mol. Genet. 27, 120-134. doi: 10.1093/hmg/ddx389
121. Oh, C. K., Sultan, A., Platzer, J., Dolatabadi, N., Soldner, F., McClatchy, D. B., et al. (2017). S-Nitrosylation of PINK1 attenuates PINK1/parkin-dependent mitophagy in hiPSC-based Parkinson's disease models. Cell Rep. 21, 2171-2182. doi: 10.1016/j.celrep.2017.10.068
122. Pan, P. Y., Li, X., Wang, J., Powell, J., Wang, Q., Zhang, Y., et al. (2017). Parkinson's disease-associated LRRK2 hyperactive kinase mutant disrupts synaptic vesicle trafficking in ventral midbrain neurons. J. Neurosci. 37, 11366-11376. doi: 10.1523/JNEUROSCI.0964-17.2017
123. Panneton, W. M., Kumar, V. B., Gan, Q., Burke, W. J., and Galvin, J. E. (2010). The neurotoxicity of DOPAL: behavioral and stereological evidence for its role in Parkinson disease pathogenesis. PLoS One 5:e15251. doi: 10.1371/journal.pone.0015251
124. Park, J., Lee, J. W., Cooper, S. C., Broxmeyer, H. E., Cannon, J. R., and Kim, C. H. (2017). Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response. J. Leukoc. Biol. 102, 1093-1102. doi: 10.1189/jlb.1A0417-147RR
125. Parnetti, L., Paciotti, S., Eusebi, P., Dardis, A., Zampieri, S., Chiasserini, D., et al. (2017). Cerebrospinal fluid beta-glucocerebrosidase activity is reduced in parkinson's disease patients. Mov. Disord. 32, 1423-1431. doi: 10.1002/mds.27136
126. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047. doi: 10.1126/science.276.5321.2045
127. Porcari, R., Proukakis, C., Waudby, C. A., Bolognesi, B., Mangione, P. P., Paton, J. F., et al. (2015). The H50Q mutation induces a 10-fold decrease in the solubility of alpha-synuclein. J. Biol. Chem. 290, 2395-2404. doi: 10.1074/jbc. M114.610527
128. Pupyshev, A. B., Korolenko, T. A., Akopyan, A. A., Amstislavskaya, T. G., and Tikhonova, M. A. (2017). Suppression of autophagy in the brain of transgenic mice with overexpression of capital A, Cyrillic53capital TE, Cyrillic-mutant alpha-synuclein as an early event at synucleinopathy progression. Neurosci. Lett. 672, 140-142. doi: 10.1016/j.neulet.2017.12.001
129. Puschmann, A., Fiesel, F. C., Caulfield, T. R., Hudec, R., Ando, M., Truban, D., et al. (2017). Heterozygous PINK1 p. G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain 140, 98-117. doi: 10.1093/brain/aww261
130. Ramsey, C. P., and Giasson, B. I. (2010). L10p and P158DEL DJ-1 mutations cause protein instability, aggregation, and dimerization impairments. J. Neurosci. Res. 88, 3111-3124. doi: 10.1002/jnr.22477
131. Rappold, P. M., Cui, M., Chesser, A. S., Tibbett, J., Grima, J. C., Duan, L., et al. (2011). Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc. Natl. Acad. Sci. U.S.A. 108, 20766-20771. doi: 10.1073/pnas.1115141108
132. Rassu, M., Del Giudice, M. G., Sanna, S., Taymans, J. M., Morari, M., Brugnoli, A., et al. (2017). Role of LRRK2 in the regulation of dopamine receptor trafficking. PLoS One 12:e0179082. doi: 10.1371/journal.pone.0179082
133. Ren, H., Fu, K., Mu, C., Zhen, X., and Wang, G. (2012). L166P mutant DJ-1 promotes cell death by dissociating Bax from mitochondrial Bcl-XL. Mol. Neurodegener. 7:40. doi: 10.1186/1750-1326-7-40
134. Rivetti di Val Cervo, P., Romanov, R. A., Spigolon, G., Masini, D., Martin-Montanez, E., Toledo, E. M., et al. (2017). Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model. Nat. Biotechnol. 35, 444-452. doi: 10.1038/nbt.3835
135. Rocha, E. M., Smith, G. A., Park, E., Cao, H., Brown, E., Hallett, P., et al. (2015). Progressive decline of glucocerebrosidase in aging and Parkinson's disease. Ann. Clin. Transl. Neurol. 2, 433-438. doi: 10.1002/acn3.177
136. Rodriguez, J. A., Ivanova, M. I., Sawaya, M. R., Cascio, D., Reyes, F. E., Shi, D., et al. (2015). Structure of the toxic core of alpha-synuclein from invisible crystals. Nature 525, 486-490. doi: 10.1038/nature15368
137. Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A., et al. (2008). Genomic investigation of alpha-synuclein multiplication and parkinsonism. Ann. Neurol. 63, 743-750. doi: 10.1002/ana.21380
138. Rutherford, N. J., Moore, B. D., Golde, T. E., and Giasson, B. I. (2014). Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of alpha-synuclein. J. Neurochem. 131, 859-867. doi: 10.1111/jnc.12806
139. Ryu, E. J., Harding, H. P., Angelastro, J. M., Vitolo, O. V., Ron, D., and Greene, L. A. (2002). Endoplasmic reticulum stress and the unfolded protein response in cellular models of Parkinson's disease. J. Neurosci. 22, 10690-10698
140. Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., et al. (2016). Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167, 1469-1480.e12. doi: 10.1016/j.cell.2016.11.018
141. Sanyal, J., Jana, A., Ghosh, E., Banerjee, T. K., Chakraborty, D. P., and Rao, V. R. (2015). Evaluation of PARKIN gene variants in West Bengal Parkinson's disease patients. J. Hum. Genet. 60, 485-492. doi: 10.1038/jhg.2015.49
142. Sanz, F. J., Solana-Manrique, C., Munoz-Soriano, V., Calap-Quintana, P., Molto, M. D., and Paricio, N. (2017). Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models. Free Radic. Biol. Med. 108, 683-691. doi: 10.1016/j.freeradbiomed.2017.04.364
143. Sato, H., Arawaka, S., Hara, S., Fukushima, S., Koga, K., Koyama, S., et al. (2011). Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease. J. Neurosci. 31, 16884-16894. doi: 10.1523/JNEUROSCI.3967-11.2011
144. Schapira, A. H. (2008). Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol. 7, 97-109. doi: 10.1016/S1474-4422(07)70327-7
145. Schnabel, J. (2010). Secrets of the shaking palsy. Nature 466, S2-S5. doi: 10.1038/466S2b
146. Schneider, S. A., and Alcalay, R. N. (2017). Neuropathology of genetic synucleinopathies with parkinsonism: review of the literature. Mov. Disord. 32, 1504-1523. doi: 10.1002/mds.27193
147. Schroder, M., and Kaufman, R. J. (2005). The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739-789. doi: 10.1146/annurev.biochem.73.011303.074134
148. Selvaraj, S., Sun, Y., Watt, J. A., Wang, S., Lei, S., Birnbaumer, L., et al. (2012). Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling. J. Clin. Invest. 122, 1354-1367. doi: 10.1172/JCI61332
149. Sheng, Y. L., Chen, X., Hou, X. O., Yuan, X., Yuan, B. S., Yuan, Y. Q., et al. (2017). Urate promotes SNCA/alpha-synuclein clearance via regulating mTOR-dependent macroautophagy. Exp. Neurol. 297, 138-147. doi: 10.1016/j.expneurol.2017.08.007
150. Sherer, T. B., Betarbet, R., Kim, J. H., and Greenamyre, J. T. (2003). Selective microglial activation in the rat rotenone model of Parkinson's disease. Neurosci. Lett. 341, 87-90. doi: 10.1016/S0304-3940(03)00172-1
151. Shields, B. C., Kahuno, E., Kim, C., Apostolides, P. F., Brown, J., Lindo, S., et al. (2017). Deconstructing behavioral neuropharmacology with cellular specificity. Science 356:aaj2161. doi: 10.1126/science.aaj2161
152. Sidransky, E., Nalls, M. A., Aasly, J. O., Aharon-Peretz, J., Annesi, G., Barbosa, E. R., et al. (2009). Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651-1661. doi: 10.1056/NEJMoa0901281
153. Smith, W. W., Jiang, H., Pei, Z., Tanaka, Y., Morita, H., Sawa, A., et al. (2005a). Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum. Mol. Genet. 14, 3801-3811
154. Smith, W. W., Pei, Z., Jiang, H., Moore, D. J., Liang, Y., West, A. B., et al. (2005b). Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. U.S.A. 102, 18676-18681
155. Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., and Goedert, M. (1997). Alpha-synuclein in Lewy bodies. Nature 388, 839-840. doi: 10.1038/42166
156. Steger, M., Diez, F., Dhekne, H. S., Lis, P., Nirujogi, R. S., Karayel, O., et al. (2017). Systematic proteomic analysis of LRRK2-mediated Rab GTPase phosphorylation establishes a connection to ciliogenesis. Elife 6:e31012. doi: 10.7554/eLife.31012
157. Sterky, F. H., Hoffman, A. F., Milenkovic, D., Bao, B., Paganelli, A., Edgar, D., et al. (2012). Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons. Hum. Mol. Genet. 21, 1078-1089. doi: 10.1093/hmg/ddr537
158. Storch, A., Ludolph, A. C., and Schwarz, J. (2004). Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration. J. Neural Transm. (Vienna). 111, 1267-1286. doi: 10.1007/s00702-004-0203-2
159. Su, P., and Liu, F. (2017). A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity. Exp. Neurol. 295, 176-183. doi: 10.1016/j.expneurol.2017.05.010
160. Su, Y. C., Guo, X., and Qi, X. (2015). Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy. Biochim. Biophys. Acta 1852, 12-21. doi: 10.1016/j.bbadis.2014.11.009
161. Subramaniam, S. R., and Chesselet, M. F. (2013). Mitochondrial dysfunction and oxidative stress in Parkinson's disease. Prog. Neurobiol. 106-107, 17-32. doi: 10.1016/j.pneurobio.2013.04.004
162. Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L., Kanter, E., Agin-Liebes, J., et al. (2017). T cells from patients with Parkinson's disease recognize alpha-synuclein peptides. Nature 546, 656-661. doi: 10.1038/nature22815
163. Taguchi, Y. V., Liu, J., Ruan, J., Pacheco, J., Zhang, X., Abbasi, J., et al. (2017). Glucosylsphingosine promotes alpha-synuclein pathology in mutant GBA-associated Parkinson's disease. J. Neurosci. 37, 9617-9631. doi: 10.1523/JNEUROSCI.1525-17.2017
164. Taipa, R., Pereira, C., Reis, I., Alonso, I., Bastos-Lima, A., Melo-Pires, M., et al. (2016). DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139, 1680-1687. doi: 10.1093/brain/aww080
165. Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., et al. (2006). Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Hum. Mol. Genet. 15, 1816-1825. doi: 10.1093/hmg/ddl104
166. Tang, F. L., Erion, J. R., Tian, Y., Liu, W., Yin, D. M., Ye, J., et al. (2015a). VPS35 in dopamine neurons is required for endosome-to-golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson's disease. J. Neurosci. 35, 10613-10628. doi: 10.1523/JNEUROSCI.0042-15.2015
167. Tang, F. L., Liu, W., Hu, J. X., Erion, J. R., Ye, J., Mei, L., et al. (2015b). VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep. 12, 1631-1643. doi: 10.1016/j.celrep.2015.08.001
168. Thomas, J. M., Li, T., Yang, W., Xue, F., Fishman, P. S., and Smith, W. W. (2016). 68 and FX2149 attenuate mutant LRRK2-R1441C-induced neural transport impairment. Front. Aging Neurosci. 8:337. doi: 10.3389/fnagi.2016.00337
169. Torres-Odio, S., Key, J., Hoepken, H. H., Canet-Pons, J., Valek, L., Roller, B., et al. (2017). Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation. J. Neuroinflammation 14:154. doi: 10.1186/s12974-017-0928-0
170. Valdes, P., Mercado, G., Vidal, R. L., Molina, C., Parsons, G., Court, F. A., et al. (2014). Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. Proc. Natl. Acad. Sci. U.S.A. 111, 6804-6809. doi: 10.1073/pnas.1321845111
171. Vanle, B. C., Florang, V. R., Murry, D. J., Aguirre, A. L., and Doorn, J. A. (2017). Inactivation of glyceraldehyde-3-phosphate dehydrogenase by the dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde. Biochem. Biophys. Res. Commun. 492, 275-281. doi: 10.1016/j.bbrc.2017.08.067
172. Verma, M., Callio, J., Otero, P. A., Sekler, I., Wills, Z. P., and Chu, C. T. (2017). Mitochondrial calcium dysregulation contributes to dendrite degeneration mediated by PD/LBD-Associated LRRK2 Mutants. J. Neurosci. 37, 11151-11165. doi: 10.1523/JNEUROSCI.3791-16.2017
173. Villar-Pique, A., Rossetti, G., Ventura, S., Carloni, P., Fernandez, C. O., and Outeiro, T. F. (2017). Copper(II) and the pathological H50Q alpha-synuclein mutant: environment meets genetics. Commun. Integr. Biol. 10:e1270484. doi: 10.1080/19420889.2016.1270484
174. Volpicelli-Daley, L. A., Abdelmotilib, H., Liu, Z., Stoyka, L., Daher, J. P., Milnerwood, A. J., et al. (2016). G2019S-LRRK2 expression ments alpha-synuclein sequestration into inclusions in neurons. J. Neurosci. 36, 7415-7427. doi: 10.1523/JNEUROSCI.3642-15.2016
175. Walter, P., and Ron, D. (2011). The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081-1086. doi: 10.1126/science.1209038
176. Wang, H. S., Toh, J., Ho, P., Tio, M., Zhao, Y., and Tan, E. K. (2014). In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila. Mol. Brain 7:73. doi: 10.1186/s13041-014-0073-y
177. Wang, K., Huang, J., Xie, W., Huang, L., Zhong, C., and Chen, Z. (2016). Beclin1 and HMGB1 ameliorate the alpha-synuclein-mediated autophagy inhibition in PC12 cells. Diagn. Pathol. 11:15. doi: 10.1186/s13000-016-0459-5
178. Wang, W., Wang, X., Fujioka, H., Hoppel, C., Whone, A. L., Caldwell, M. A., et al. (2016). Parkinson's disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes. Nat. Med. 22, 54-63. doi: 10.1038/nm.3983
179. Wang, X., Yan, M. H., Fujioka, H., Liu, J., Wilson-Delfosse, A., Chen, S. G., et al. (2012). LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum. Mol. Genet. 21, 1931-1944. doi: 10.1093/hmg/dds003
180. West, A. B. (2017). Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp. Neurol. 298, 236-245. doi: 10.1016/j.expneurol.2017.07.019
181. Winner, B., Jappelli, R., Maji, S. K., Desplats, P. A., Boyer, L., Aigner, S., et al. (2011). In vivo demonstration that alpha-synuclein oligomers are toxic. Proc. Natl. Acad. Sci. U.S.A. 108, 4194-4199. doi: 10.1073/pnas.1100976108
182. Xiao, B., Goh, J. Y., Xiao, L., Xian, H., Lim, K. L., and Liou, Y. C. (2017). Reactive oxygen species trigger Parkin/PINK1 pathway-dependent mitophagy by inducing mitochondrial recruitment of Parkin. J. Biol. Chem. 292, 16697-16708. doi: 10.1074/jbc. M117.787739
183. Xilouri, M., Brekk, O. R., Polissidis, A., Chrysanthou-Piterou, M., Kloukina, I., and Stefanis, L. (2016). Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats. Autophagy 12, 2230-2247. doi: 10.1080/15548627.2016.1214777
184. Xu, C. Y., Kang, W. Y., Chen, Y. M., Jiang, T. F., Zhang, J., Zhang, L. N., et al. (2017). DJ-1 inhibits alpha-synuclein aggregation by regulating chaperone-mediated autophagy. Front. Aging Neurosci. 9:308. doi: 10.3389/fnagi.2017.00308
185. Yan, J. Q., Yuan, Y. H., Gao, Y. N., Huang, J. Y., Ma, K. L., Gao, Y., et al. (2014). Overexpression of human E46K mutant alpha-synuclein impairs macroautophagy via inactivation of JNK1-Bcl-2 pathway. Mol. Neurobiol. 50, 685-701. doi: 10.1007/s12035-014-8738-1
186. Yan, M. H., Wang, X., and Zhu, X. (2013). Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med. 62, 90-101. doi: 10.1016/j.freeradbiomed.2012.11.014
187. Yin, F., Boveris, A., and Cadenas, E. (2014). Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid. Redox Signal. 20, 353-371. doi: 10.1089/ars.2012.4774
188. Yoon, J. H., Mo, J. S., Kim, M. Y., Ann, E. J., Ahn, J. S., Jo, E. H., et al. (2017). LRRK2 functions as a scaffolding kinase of ASK1-mediated neuronal cell death. Biochim. Biophys. Acta 1864, 2356-2368. doi: 10.1016/j.bbamcr.2017.09.001
189. Yun, S. P., Kim, H., Ham, S., Kwon, S. H., Lee, G. H., Shin, J. H., et al. (2017). VPS35 regulates parkin substrate AIMP2 toxicity by facilitating lysosomal clearance of AIMP2. Cell Death Dis. 8:e2741. doi: 10.1038/cddis.2017.157
190. Zeng, X. S., Jia, J. J., Kwon, Y., Wang, S. D., and Bai, J. (2014). The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radic. Biol. Med. 67, 10-18. doi: 10.1016/j.freeradbiomed.2013.10.013
191. Zhang, S., Eitan, E., Wu, T. Y., and Mattson, M. P. (2018). Intercellular transfer of pathogenic alpha-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol. Aging 61, 52-65. doi: 10.1016/j.neurobiolaging.2017.09.016
192. Zhang, W., Dallas, S., Zhang, D., Guo, J. P., Pang, H., Wilson, B., et al. (2007). Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein. Glia 55, 1178-1188. doi: 10.1002/glia.20532
193. Zhang, Y., Gong, X. G., Wang, Z. Z., Sun, H. M., Guo, Z. Y., Hu, J. H., et al. (2016). Overexpression of DJ-1/PARK7, the Parkinson's disease-related protein, improves mitochondrial function via Akt phosphorylation on threonine 308 in dopaminergic neuron-like cells. Eur. J. Neurosci. 43, 1379-1388. doi: 10.1111/ejn.13216
194. Zhang, Z., Chu, S. F., Wang, S. S., Jiang, Y. N., Gao, Y., Yang, P. F., et al. (2017). RTP801 is a critical factor in the neurodegeneration process of A53T alpha-synuclein in a mouse model of Parkinson's disease under chronic restraint stress. Br. J. Pharmacol. 175, 590-605. doi: 10.1111/bph.14091
195. Zhao, H. T., John, N., Delic, V., Ikeda-Lee, K., Kim, A., Weihofen, A., et al. (2017). LRRK2 antisense oligonucleotides ameliorate alpha-synuclein inclusion formation in a Parkinson's disease mouse model. Mol. Ther. Nucleic Acids 8, 508-519. doi: 10.1016/j.omtn.2017.08.002
196. Zharikov, A. D., Cannon, J. R., Tapias, V., Bai, Q., Horowitz, M. P., Shah, V., et al. (2015). shRNA targeting alpha-synuclein prevents neurodegeneration in a Parkinson's disease model. J. Clin. Invest. 125, 2721-2735. doi: 10.1172/JCI64502
197. Zhou, L., Wang, W., Hoppel, C., Liu, J., and Zhu, X. (2017). Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits. Biochim. Biophys. Acta 1863, 2791-2795. doi: 10.1016/j.bbadis.2017.07.032
198. Zhou, Z. D., Kerk, S. Y., Xiong, G. G., and Lim, T. M. (2009). Dopamine auto-oxidation aggravates non-apoptotic cell death induced by over-expression of human A53T mutant alpha-synuclein in dopaminergic PC12 cells. J. Neurochem. 108, 601-610. doi: 10.1111/j.1471-4159.2008.05795.x
199. Zhu, M. S., H Patel, S., and Han, S. (2017). DJ-1, a Parkinson's disease related protein, aggregates under denaturing conditions and co-aggregates with alpha-synuclein through hydrophobic interaction. Biochim. Biophys. Acta 1861, 1759-1769. doi: 10.1016/j.bbagen.2017.03.013
200. Zhuang, N., Li, L., Chen, S., and Wang, T. (2016). PINK1-dependent phosphorylation of PINK1 and Parkin is essential for mitochondrial quality control. Cell Death Dis. 7:e2501. doi: 10.1038/cddis.2016.396
201. Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601-607. doi: 10.1016/j.neuron.2004.11.005
202. Zondler, L., Kostka, M., Garidel, P., Heinzelmann, U., Hengerer, B., Mayer, B., et al. (2017). Proteasome impairment by alpha-synuclein. PLoS One 12:e0184040. doi: 10.1371/journal.pone.0184040
203. Zondler, L., Miller-Fleming, L., Repici, M., Goncalves, S., Tenreiro, S., Rosado-Ramos, R., et al. (2014). DJ-1 interactions with alpha-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease. Cell Death Dis. 5:e1350. doi: 10.1038/cddis.2014.307