F. Aim of this study
V. SUMMARY AND CONCLUSION
I described two major findings in this thesis:
1. DJ-1 deficiency attenuates endogenous repair through insufficient astrogliosis via STAT3 phosphorylation
2. DJ-1 deficiency attenuates the anti-inflammatory function of astrocytes through the reduction of L-PGDS expression as a result of excess Sox9 ubiquitination.
Recently, many studies have demonstrated that non-neuronal cell dysfunction is also related to neurodegenerative diseases, although the diseases are caused by neuronal cell death since the functions of non-neuronal cells are still found in numerous neuropathological conditions. Here, I also found that the PD-related gene DJ-1 regulated numerous functions of astrocytes. Therefore, studies of non-neuronal cells could provide greater information about the progression of PD and help identify new therapeutic targets.
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REFERENCES
1. Abbott, N.J. Astrocyte-endothelial interactions and blood-brain barrier permeability.
Journal of anatomy 200, 629-638 (2002).
2. Abbott, N.J. & Friedman, A. Overview and introduction: the blood-brain barrier in health and disease. Epilepsia 53 Suppl 6, 1-6 (2012).
3. Abou-Sleiman, P.M., Healy, D.G., Quinn, N., Lees, A.J. & Wood, N.W. The role of pathogenic DJ-1 mutations in Parkinson's disease. Annals of neurology 54, 283-286 (2003).
4. Ageta-Ishihara, N. et al. Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. Mol Brain 6, 35 (2013).
5. Ajuebor, M.N., Singh, A. & Wallace, J.L. Cyclooxygenase-2-derived prostaglandin D(2) is an early anti-inflammatory signal in experimental colitis. American journal of physiology. Gastrointestinal and liver physiology 279, G238-244 (2000).
6. Akiyama, H. et al. The transcription factor Sox9 is degraded by the ubiquitin-proteasome system and stabilized by a mutation in a ubiquitin-target site. Matrix biology : journal of the International Society for Matrix Biology 23, 499-505 (2005).
7. Akiyama, M., Matsuda, Y., Ishiwata, T., Naito, Z. & Kawana, S. Inhibition of the stem cell marker nestin reduces tumor growth and invasion of malignant melanoma.
The Journal of investigative dermatology 133, 1384-1387 (2013).
8. Albrecht, P.J. et al. Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production.
Neurobiology of disease 13, 89-101 (2003).
9. Amadio, S. et al. P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 42, 489-501 (2002).
10. Araque, A., Parpura, V., Sanzgiri, R.P. & Haydon, P.G. Tripartite synapses: glia, the unacknowledged partner. Trends in neurosciences 22, 208-215 (1999a).
11. Araque, A., Sanzgiri, R.P., Parpura, V. & Haydon, P.G. Astrocyte-induced modulation of synaptic transmission. Canadian journal of physiology and pharmacology 77, 699-706 (1999b).
12. Arenas, E., Trupp, M., Akerud, P. & Ibanez, C.F. GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron 15,
1465-８７ human putamen affected by Parkinson's disease: a real-time PCR study. Molecular and cellular endocrinology 252, 160-166 (2006).
15. Bader, V., Ran Zhu, X., Lubbert, H. & Stichel, C.C. Expression of DJ-1 in the adult mouse CNS. Brain research 1041, 102-111 (2005).
16. Bandopadhyay, R. et al. The expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease. Brain : a journal of neurology 127, 420-430 (2004).
17. Banker, G.A. Trophic interactions between astroglial cells and hippocampal neurons in culture. Science 209, 809-810 (1980).
18. Barbosa, E.R. Non-motor symptoms in Parkinson's disease. Arquivos de neuro-psiquiatria 71, 203-204 (2013).
19. Batchelor, P.E., Liberatore, G.T., Porritt, M.J., Donnan, G.A. & Howells, D.W.
Inhibition of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum. The European journal of neuroscience 12, 3462-3468 (2000).
20. Batchelor, P.E. et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. The Journal of neuroscience : the official journal of the Society for Neuroscience 19, 1708-1716 (1999).
21. Beilina, A. et al. Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability. Proceedings of the National Academy of Sciences of the United States of America 102, 5703-5708 (2005).
22. Benfey, M. & Aguayo, A.J. Extensive elongation of axons from rat brain into peripheral nerve grafts. Nature 296, 150-152 (1982).
23. Beschorner, R. et al. Long-term expression of heme oxygenase-1 (HO-1, HSP-32) following focal cerebral infarctions and traumatic brain injury in humans. Acta neuropathologica 100, 377-384 (2000).
８８
24. Bjorklund, A., Rosenblad, C., Winkler, C. & Kirik, D. Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease.
Neurobiology of disease 4, 186-200 (1997).
25. Blackinton, J.G. et al. Expression of PINK1 mRNA in human and rodent brain and in Parkinson's disease. Brain Res 1184, 10-16 (2007).
26. Bonifati, V. et al. DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 24, 159-160 (2003a).
27. Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256-259 (2003b).
28. Breitner, J.C. The role of anti-inflammatory drugs in the prevention and treatment of Alzheimer's disease. Annual review of medicine 47, 401-411 (1996).
29. Bristol, L.A. & Rothstein, J.D. Glutamate transporter gene expression in amyotrophic lateral sclerosis motor cortex. Annals of neurology 39, 676-679 (1996).
30. Bruijn, L.I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327-338 (1997).
31. Buffo, A. et al. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proceedings of the National Academy of Sciences of the United States of America 105, 3581-3586 (2008).
32. Buj-Bello, A., Buchman, V.L., Horton, A., Rosenthal, A. & Davies, A.M. GDNF is an age-specific survival factor for sensory and autonomic neurons. Neuron 15, 821-828 (1995).
33. Burda, J.E. & Sofroniew, M.V. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81, 229-248 (2014).
34. Burke, R.E., Antonelli, M. & Sulzer, D. Glial cell line-derived neurotrophic growth factor inhibits apoptotic death of postnatal substantia nigra dopamine neurons in primary culture. Journal of neurochemistry 71, 517-525 (1998).
35. Cavaliere, F. et al. Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists. Neurochemistry international 38, 189-197 (2001a).
36. Cavaliere, F., D'Ambrosi, N., Sancesario, G., Bernardi, G. & Volonte, C.
Hypoglycaemia-induced cell death: features of neuroprotection by the P2 receptor antagonist basilen blue. Neurochemistry international 38, 199-207 (2001b).
８９
37. Chao, C.C., Hu, S., Molitor, T.W., Shaskan, E.G. & Peterson, P.K. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol 149, 2736-2741 (1992).
38. Chartier-Harlin, M.C. et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169 (2004).
39. Chen, H. et al. Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Archives of neurology 60, 1059-1064 (2003).
40. Chen, L. et al. Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. The Journal of biological chemistry 280, 21418-21426 (2005).
41. Chen, Y. et al. Astrocytes protect neurons from nitric oxide toxicity by a glutathione-dependent mechanism. Journal of neurochemistry 77, 1601-1610 (2001).
42. Cherra, S.J., 3rd, Steer, E., Gusdon, A.M., Kiselyov, K. & Chu, C.T. Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol 182, 474-484 (2013).
43. Chiba, M., Kiyosawa, H., Hiraiwa, N., Ohkohchi, N. & Yasue, H. Existence of Pink1 antisense RNAs in mouse and their localization. Cytogenet Genome Res 126, 259-270 (2009).
44. Chih, C.P. & Roberts Jr, E.L. Energy substrates for neurons during neural activity: a critical review of the astrocyte-neuron lactate shuttle hypothesis. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 23, 1263-1281 (2003).
45. Choi, I. et al. LRRK2 G2019S mutation attenuates microglial motility by inhibiting focal adhesion kinase. Nature communications 6, 8255 (2015).
46. Choi, I. et al. Pink1 deficiency attenuates astrocyte proliferation through mitochondrial dysfunction, reduced akt and increased p38 mapk activation, and downregulation of egfr. Glia 61, 800-812 (2013).
47. Choi, S.H., Joe, E.H., Kim, S.U. & Jin, B.K. Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 5877-5886 (2003).
48. Chung, K.K. et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7, 1144-1150 (2001).
９０
49. Clements, C.M., McNally, R.S., Conti, B.J., Mak, T.W. & Ting, J.P. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences of the United States of America 103, 15091-15096 (2006).
50. Compston, A. Brain repair. Journal of internal medicine 237, 127-134 (1995).
51. Correa-Cerro, L.S. & Mandell, J.W. Molecular mechanisms of astrogliosis: new approaches with mouse genetics. Journal of neuropathology and experimental neurology 66, 169-176 (2007).
52. Corti, O. et al. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum Mol Genet 12, 1427-1437 (2003).
53. Covy, J.P. et al. Clinical and pathological characteristics of patients with leucine-rich repeat kinase-2 mutations. Movement disorders : official journal of the Movement Disorder Society 24, 32-39 (2009).
54. Cregg, J.M. et al. Functional regeneration beyond the glial scar. Experimental neurology 253, 197-207 (2014).
55. Cui, W., Allen, N.D., Skynner, M., Gusterson, B. & Clark, A.J. Inducible ablation of astrocytes shows that these cells are required for neuronal survival in the adult brain.
Glia 34, 272-282 (2001).
56. d'Amora, M. et al. Expression of PINK1 in the brain, eye and ear of mouse during embryonic development. J Chem Neuroanat 41, 73-85 (2011).
57. Dabir, D.V. et al. Impaired glutamate transport in a mouse model of tau pathology in astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 26, 644-654 (2006).
58. Dallner, C., Woods, A.G., Deller, T., Kirsch, M. & Hofmann, H.D. CNTF and CNTF receptor alpha are constitutively expressed by astrocytes in the mouse brain. Glia 37, 374-378 (2002).
59. Damier, P., Hirsch, E.C., Agid, Y. & Graybiel, A.M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain : a journal of neurology 122 ( Pt 8), 1437-1448 (1999).
60. Daneman, R. The blood-brain barrier in health and disease. Annals of neurology 72, 648-672 (2012).
61. David, S. & Aguayo, A.J. Axonal elongation into peripheral nervous system
９１
"bridges" after central nervous system injury in adult rats. Science 214, 931-933 (1981).
62. Dawson, T.M. & Dawson, V.L. Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819-822 (2003).
63. Deng, H., Jankovic, J., Guo, Y., Xie, W. & Le, W. Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y. Biochemical and biophysical research communications 337, 1133-1138 (2005).
64. Dennery, P.A. et al. Heme oxygenase-mediated resistance to oxygen toxicity in hamster fibroblasts. The Journal of biological chemistry 272, 14937-14942 (1997).
65. Dervan, A.G. et al. Astroglial plasticity and glutamate function in a chronic mouse model of Parkinson's disease. Experimental neurology 190, 145-156 (2004).
66. Desagher, S., Glowinski, J. & Premont, J. Astrocytes protect neurons from hydrogen peroxide toxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 16, 2553-2562 (1996).
67. Desai Bradaric, B., Patel, A., Schneider, J.A., Carvey, P.M. & Hendey, B. Evidence for angiogenesis in Parkinson's disease, incidental Lewy body disease, and progressive supranuclear palsy. J Neural Transm (Vienna) 119, 59-71 (2012).
68. DeWitt, D.A., Perry, G., Cohen, M., Doller, C. & Silver, J. Astrocytes regulate microglial phagocytosis of senile plaque cores of Alzheimer's disease. Experimental neurology 149, 329-340 (1998).
69. Ding, A.H., Nathan, C.F. & Stuehr, D.J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J Immunol 141, 2407-2412 (1988).
70. Ding, S. Dynamic reactive astrocytes after focal ischemia. Neural regeneration research 9, 2048-2052 (2014).
71. do Carmo Cunha, J. et al. Responses of reactive astrocytes containing S100beta protein and fibroblast growth factor-2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: implications for wound repair and neuroregeneration. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society 15, 134-146 (2007).
72. Doetsch, F., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Cellular composition and
９２
three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 17, 5046-5061 (1997).
73. Dringen, R. & Hamprecht, B. Glucose, insulin, and insulin-like growth factor I regulate the glycogen content of astroglia-rich primary cultures. Journal of neurochemistry 58, 511-517 (1992).
74. Du, Y. et al. Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 98, 14669-14674 (2001).
75. Duan, C.L. et al. Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury. Glia 63, 1660-1670 (2015).
76. Eddleston, M. & Mucke, L. Molecular profile of reactive astrocytes--implications for their role in neurologic disease. Neuroscience 54, 15-36 (1993).
77. Eguchi, N. et al. Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 96, 726-730 (1999).
78. Elkabes, S., DiCicco-Bloom, E.M. & Black, I.B. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function.
The Journal of neuroscience : the official journal of the Society for Neuroscience 16, 2508-2521 (1996).
79. Eng, L.F. & Ghirnikar, R.S. GFAP and astrogliosis. Brain Pathol 4, 229-237 (1994).
80. Eng, L.F., Ghirnikar, R.S. & Lee, Y.L. Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochemical research 25, 1439-1451 (2000).
81. Fan, J. et al. DJ-1 decreases Bax expression through repressing p53 transcriptional activity. The Journal of biological chemistry 283, 4022-4030 (2008).
82. Fitch, M.T. & Silver, J. Activated macrophages and the blood-brain barrier:
inflammation after CNS injury leads to increases in putative inhibitory molecules.
Experimental neurology 148, 587-603 (1997).
83. Gandhi, S. et al. PINK1 protein in normal human brain and Parkinson's disease.
Brain 129, 1720-1731 (2006).
84. Gandhi, S. et al. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Molecular cell 33, 627-638 (2009).
85. Gardet, A. et al. LRRK2 is involved in the IFN-gamma response and host response
９３
to pathogens. J Immunol 185, 5577-5585 (2010).
86. Gardner-Medwin, A.R. Analysis of potassium dynamics in mammalian brain tissue.
The Journal of physiology 335, 393-426 (1983).
87. Garg, S.K., Banerjee, R. & Kipnis, J. Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective phenotype. J Immunol 180, 3866-3873 (2008).
88. Gash, D.M. et al. Functional recovery in parkinsonian monkeys treated with GDNF.
Nature 380, 252-255 (1996).
89. Gilroy, D.W. et al. Inducible cyclooxygenase may have anti-inflammatory properties.
Nature medicine 5, 698-701 (1999).
90. Gispert, S. et al. Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PloS one 4, e5777 (2009).
91. Glezer, I., Simard, A.R. & Rivest, S. Neuroprotective role of the innate immune system by microglia. Neuroscience 147, 867-883 (2007).
92. Goldberg, M.S. et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. The Journal of biological chemistry 278, 43628-43635 (2003).
93. Gomez-Suaga, P., Churchill, G.C., Patel, S. & Hilfiker, S. A link between LRRK2, autophagy and NAADP-mediated endolysosomal calcium signalling. Biochem Soc Trans 40, 1140-1146 (2012).
94. Gomez-Suaga, P. & Hilfiker, S. LRRK2 as a modulator of lysosomal calcium homeostasis with downstream effects on autophagy. Autophagy 8, 692-693 (2012).
95. Gomi, H. et al. Mice devoid of the glial fibrillary acidic protein develop normally and are susceptible to scrapie prions. Neuron 14, 29-41 (1995).
96. Gotz, M., Sirko, S., Beckers, J. & Irmler, M. Reactive astrocytes as neural stem or progenitor cells: In vivo lineage, In vitro potential, and Genome-wide expression analysis. Glia 63, 1452-1468 (2015).
97. Gu, X.L. et al. Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice. Molecular brain 3, 12 (2010).
98. Haque, M.E. et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP. Proceedings of the National Academy of Sciences of the United States of America 105, 1716-1721 (2008).
９４
99. Haughey, N.J. & Mattson, M.P. Alzheimer's amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular medicine 3, 173-180 (2003).
100. He, Y., Appel, S. & Le, W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain research 909, 187-193 (2001).
101. Heinrich, C. et al. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS biology 8, e1000373 (2010).
102. Hering, R. et al. Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Human mutation 24, 321-329 (2004).
103. Hernandez, M.R. et al. Differential gene expression in astrocytes from human normal and glaucomatous optic nerve head analyzed by cDNA microarray. Glia 38, 45-64 (2002).
104. Herrmann, J.E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 7231-7243 (2008).
105. Howland, D.S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).
Proceedings of the National Academy of Sciences of the United States of America 99, 1604-1609 (2002).
106. Iannotti, C. et al. Glial cell line-derived neurotrophic factor-enriched bridging transplants promote propriospinal axonal regeneration and enhance myelination after spinal cord injury. Experimental neurology 183, 379-393 (2003).
107. Imai, Y. et al. CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol Cell 10, 55-67 (2002).
108. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891-902 (2001).
109. Jaleel, M. et al. LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity. The Biochemical journal 405, 307-317 (2007).
110. Jensen, C.J., Massie, A. & De Keyser, J. Immune players in the CNS: the astrocyte.
Journal of neuroimmune pharmacology : the official journal of the Society on
９５
NeuroImmune Pharmacology 8, 824-839 (2013).
111. Jeong, H.K., Ji, K., Min, K. & Joe, E.H. Brain inflammation and microglia: facts and misconceptions. Experimental neurobiology 22, 59-67 (2013a).
112. Jeong, H.K. et al. Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury. PloS one 5, e13756 (2010).
113. Jeong, H.K., Ji, K.M., Kim, J., Jou, I. & Joe, E.H. Repair of astrocytes, blood vessels, and myelin in the injured brain: possible roles of blood monocytes. Molecular brain 6, 28 (2013b).
114. John, G.R., Lee, S.C., Song, X., Rivieccio, M. & Brosnan, C.F. IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 49, 161-176 (2005).
115. Johnston, J.M., Burnett, P., Thomas, A.P. & Tezapsidis, N. Calcium oscillations in type-1 astrocytes, the effect of a presenilin 1 (PS1) mutation. Neuroscience letters 395, 159-164 (2006).
116. Jowsey, I.R. et al. Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases. The Biochemical journal 359, 507-516 (2001).
117. Junn, E. et al. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Proceedings of the National Academy of Sciences of the United States of America 102, 9691-9696 (2005).
118. Justicia, C., Gabriel, C. & Planas, A.M. Activation of the JAK/STAT pathway following transient focal cerebral ischemia: signaling through Jak1 and Stat3 in astrocytes. Glia 30, 253-270 (2000).
119. Kapturczak, M.H. et al. Heme oxygenase-1 modulates early inflammatory responses:
evidence from the heme oxygenase-1-deficient mouse. The American journal of pathology 165, 1045-1053 (2004).
120. Kim, B. et al. Impaired inflammatory responses in murine Lrrk2-knockdown brain microglia. PloS one 7, e34693 (2012).
121. Kim, J.H. et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1. Neurobiology of disease 60, 1-10 (2013a).
122. Kim, K.S. et al. DJ-1 associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes. Human molecular genetics 22, 4805-4817 (2013b).
９６
123. Kim, R.H. et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proceedings of the National Academy of Sciences of the United States of America 102, 5215-5220 (2005).
124. Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605-608 (1998).
125. Kitada, T., Tong, Y., Gautier, C.A. & Shen, J. Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. Journal of neurochemistry 111, 696-702 (2009).
126. Kitamura, Y. et al. In vivo induction of inducible nitric oxide synthase by microinjection with interferon-gamma and lipopolysaccharide in rat hippocampus.
Glia 18, 233-243 (1996).
127. Klegeris, A. & McGeer, P.L. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease.
Current Alzheimer research 2, 355-365 (2005).
128. Knott, C., Stern, G. & Wilkin, G.P. Inflammatory regulators in Parkinson's disease:
iNOS, lipocortin-1, and cyclooxygenases-1 and -2. Molecular and cellular neurosciences 16, 724-739 (2000).
129. Koistinaho, J. et al. Long-term induction of haem oxygenase-1 (HSP-32) in astrocytes and microglia following transient focal brain ischaemia in the rat. The European journal of neuroscience 8, 2265-2272 (1996).
130. Kondapalli, C. et al. PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65.
Open Biol 2, 120080 (2012).
131. Kordower, J.H. et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767-773 (2000).
132. Kotaria, N., Hinz, U., Zechel, S. & von Bohlen Und Halbach, O. Localization of DJ-1 protein in the murine brain. Cell and tissue research 322, 503-507 (2005).
133. Krum, J.M. & Rosenstein, J.M. VEGF mRNA and its receptor flt-1 are expressed in reactive astrocytes following neural grafting and tumor cell implantation in the adult CNS. Experimental neurology 154, 57-65 (1998).
134. Kuesap, J. et al. Prostaglandin D2 induces heme oxygenase-1 in human retinal pigment epithelial cells. Biochemical and biophysical research communications 367,
９７ 413-419 (2008).
135. Larsson, O.M., Hertz, L. & Schousboe, A. GABA uptake in astrocytes in primary cultures: coupling with two sodium ions. Journal of neuroscience research 5, 469-477 (1980).
136. Lee, M.K. et al. Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 99, 8968-8973 (2002).
137. Lee, P.J., Alam, J., Wiegand, G.W. & Choi, A.M. Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proceedings of the National Academy of Sciences of the United States of America 93, 10393-10398 (1996).
138. Lee, S. et al. Channel-mediated tonic GABA release from glia. Science 330, 790-796 (2010).
139. Lehrmann, E. et al. Microglia and macrophages are major sources of locally produced transforming growth factor-beta1 after transient middle cerebral artery occlusion in rats. Glia 24, 437-448 (1998).
140. Lendahl, U., Zimmerman, L.B. & McKay, R.D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585-595 (1990).
140. Lendahl, U., Zimmerman, L.B. & McKay, R.D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585-595 (1990).