ログイン
ランキング
お知らせ
ログイン
文献詳細
総説
アストロサイトとニューロンの代謝コンパートメントからみたパーキンソン病の病態と治療
著者： 髙橋愼一1 関守信1 鈴木則宏1
所属機関： 1慶應義塾大学医学部神経内科
ページ範囲：P.1497 - P.1508
文献概要
はじめに
パーキンソン病（Parkinson disease：PD）は，黒質緻密層のドパミンニューロンの変性・脱落に伴って生じる線条体ドパミン量低下に伴う運動症状を中核とする変性疾患である1)。黒質ドパミンニューロンの変性が，いかにして惹起されるかについて完全に明らかとなったわけではないが，ミトコンドリア機能障害が関与する証左が集積されている2-4)。特発性PDにおけるミトコンドリア機能異常は，1989年，Schapiraら5)によって，PD患者の剖検脳において呼吸鎖複合体Ⅰの機能低下として生化学的手法から明らかにされ，同年，わが国のMizunoら6)も呼吸鎖複合体Ⅰの免疫ブロッティング低下から同様の結論を導いている。実験的PDモデルに用いられるMPTP（1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine）は，代謝後にMPP+として選択的な複合体Ⅰ阻害作用を呈し，MPTP全身投与は黒質ドパミンニューロンの選択的障害とともにパーキンソン症状を惹起する7)。
特発性PDの病理学的な疾患ホールマークと考えられるレヴィ小体，その構成成分であるαシヌクレインとミトコンドリア機能異常の密接な関連についても知見が集積しつつある8-11)。また，家族性PDにおいてもミトコンドリア機能異常が示唆されており12-13)，現在までに同定された変異遺伝子（座）（Table：PARK1～18）およびその産物の機能解析から，少なくともparkin（PARK2)14)，PINK1（PARK6)15)，DJ-1（PARK7)16)，LRRK2（PARK8)17)，Omi/HtrA2（PARK13)18)でミトコンドリア機能異常との関連が示されている。
ミトコンドリア機能障害と活性酸素種（reactive oxygen species：ROS）は正常者の老化とも密接に関連し19,20)，加齢を最大のリスクファクターとする特発性PD21,22)のみならず，若年者にも発症しうる家族性PDの双方においてミトコンドリア機能異常が重要な役割を果たすと推論することは理に適っている。ミトコンドリアはATP産生の場であり，脳はもともと高いエネルギー代謝を持つ臓器であるため，グルコースを基質としたエネルギー代謝に伴うROSによる酸化ストレスを受けやすい23-25)。脳は，酸化ストレスへの生得的な内因性保護機構を有すると考えられるが，特発性PD，家族性PDともにその破綻の結果とも解釈できる。
本稿では，ニューロンにおけるグルコース代謝のサポートと酸化ストレスへの保護機構の中核をなすアストロサイトの生理機能に注目し，PDのミトコンドリア機能障害仮説と治療戦略を，ニューロンとアストロサイトからなる代謝コンパートメントからまとめる。
パーキンソン病（Parkinson disease：PD）は，黒質緻密層のドパミンニューロンの変性・脱落に伴って生じる線条体ドパミン量低下に伴う運動症状を中核とする変性疾患である1)。黒質ドパミンニューロンの変性が，いかにして惹起されるかについて完全に明らかとなったわけではないが，ミトコンドリア機能障害が関与する証左が集積されている2-4)。特発性PDにおけるミトコンドリア機能異常は，1989年，Schapiraら5)によって，PD患者の剖検脳において呼吸鎖複合体Ⅰの機能低下として生化学的手法から明らかにされ，同年，わが国のMizunoら6)も呼吸鎖複合体Ⅰの免疫ブロッティング低下から同様の結論を導いている。実験的PDモデルに用いられるMPTP（1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine）は，代謝後にMPP+として選択的な複合体Ⅰ阻害作用を呈し，MPTP全身投与は黒質ドパミンニューロンの選択的障害とともにパーキンソン症状を惹起する7)。
特発性PDの病理学的な疾患ホールマークと考えられるレヴィ小体，その構成成分であるαシヌクレインとミトコンドリア機能異常の密接な関連についても知見が集積しつつある8-11)。また，家族性PDにおいてもミトコンドリア機能異常が示唆されており12-13)，現在までに同定された変異遺伝子（座）（Table：PARK1～18）およびその産物の機能解析から，少なくともparkin（PARK2)14)，PINK1（PARK6)15)，DJ-1（PARK7)16)，LRRK2（PARK8)17)，Omi/HtrA2（PARK13)18)でミトコンドリア機能異常との関連が示されている。
ミトコンドリア機能障害と活性酸素種（reactive oxygen species：ROS）は正常者の老化とも密接に関連し19,20)，加齢を最大のリスクファクターとする特発性PD21,22)のみならず，若年者にも発症しうる家族性PDの双方においてミトコンドリア機能異常が重要な役割を果たすと推論することは理に適っている。ミトコンドリアはATP産生の場であり，脳はもともと高いエネルギー代謝を持つ臓器であるため，グルコースを基質としたエネルギー代謝に伴うROSによる酸化ストレスを受けやすい23-25)。脳は，酸化ストレスへの生得的な内因性保護機構を有すると考えられるが，特発性PD，家族性PDともにその破綻の結果とも解釈できる。
本稿では，ニューロンにおけるグルコース代謝のサポートと酸化ストレスへの保護機構の中核をなすアストロサイトの生理機能に注目し，PDのミトコンドリア機能障害仮説と治療戦略を，ニューロンとアストロサイトからなる代謝コンパートメントからまとめる。
参考文献
1) Halliday GM, McRitchie DA, Cartwright H, Pamphlett R, Hely MA, et al: Midbrain neuropathology in idiopathic Parkinson's disease and diffuse Lewy body disease. J Clin Neurosci 3: 52-60, 1996
2) Schapira AH: Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol 7: 97-109, 2008
3) Schapira AH: Targeting mitochondria for neuroprotection in Parkinson's disease. Antioxid Redox Signal 16: 965-973, 2012
4) 斉木臣二: パーキンソン病はミトコンドリア障害か？「Yes」の立場から. Frontiers in Parkinson Disease 5: 78-81, 2012
5) Schapira AH, Cooper JM, Dexter D, Jenner P, Clark JB, et al: Mitochondrial complex I deficiency in Parkinson's disease. Lancet 1(8649): 1269, 1989
6) Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, et al: Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun 163: 1450-1455, 1989
7) Denton T, Howard BD: A dopaminergic cell line variant resistant to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49: 622-630, 1987
8) Gibb WR, Lees AJ: The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 51: 745-752, 1988
9) Dickson DW, Braak H, Duda JE, Duyckaerts C, Gasser T, et al: Neuropathological assessment of Parkinson's disease: refining the diagnostic criteria. Lancet Neurol 8: 1150-1157, 2009
10) Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, et al: Parkinson's disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26: 41-50, 2006
11) Esteves AR, Arduíno DM, Silva DF, Oliveira CR, Cardoso SM: Mitochondrial dysfunction: the road to alpha-synuclein oligomerization in PD. Parkinsons Dis Article ID693761, 2011．doi: 10.4061/2011/693761
12) Sai Y, Zou Z, Peng K, Dong Z: The Parkinson's disease-related genes act in mitochondrial homeostasis. Neurosci Biobehav Rev 36: 2034-2043, 2012
13) Trancikova A, Tsika E, Moore DJ: Mitochondrial dysfunction in genetic animal models of Parkinson's disease. Antioxid Redox Signal 16: 896-919, 2012
14) Palacino JJ, Sagi D, Goldberg MS, Krauss S, Motz C, et al: Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J Biol Chem 279: 18614-18622, 2004
15) Clark IE, Dodson MW, Jiang C, Cao JH, Huh JR, et al: Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441: 1162-1166, 2006
16) Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco TM, et al: DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci U S A 104: 14807-14812, 2007
17) West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, et al: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 102: 16842-16847, 2005
18) Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, et al: Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 14: 2099-2111, 2005
19) Bratic A, Larsson NG: The role of mitochondria in aging. J Clin Invest 123: 951-957, 2013
20) Kregel KC, Zhang HJ: An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 292: R18-36, 2007
21) Calne DB, Langston JW: Aetiology of Parkinson's disease. Lancet 2(8365-8366): 1457-1459, 1983
22) Vanitallie TB: Parkinson disease: primacy of age as a risk factor for mitochondrial dysfunction. Metabolism Clinical and Experimental 57(Suppl 2): S50-55, 2008
23) Clarke DD, Sokoloff L: Circulation and energy metabolism of the brain. Siegel G, Agranoff B, Albers RW, Fisher S (eds): Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 6th ed. Lippincott-Raven, Philadelphia, 1999, pp637-669
24) Dienel GA: Energy metabolism in the brain. Byrne JH, Roberts JL (eds): From Molecules to Networks: an Introduction to Cellular and Molecular Neuroscience, 2nd ed. Academic Press, London, 2009, pp49-110
25) Kann O, Kovács R: Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292: C641-657, 2007
26) 髙橋愼一: 脳の機能活動とエネルギー産生の時間的, 空間的プロファイル――ニューロン-アストロサイト連関から見たグルコース代謝. 脳循環代謝9: 1-17, 1997
27) 髙橋愼一: 脳循環代謝に関する最近の知見――ニューロン-アストロサイト-微小循環のネットワーク. 慶應医学82: 119-127, 2005
28) Madsen PL, Cruz NF, Sokoloff L, Dienel GA: Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J Cereb Blood Flow Metab 19: 393-400, 1999
29) Fox PT, Raichle ME, Mintun MA, Dence C: Nonoxidative glucose consumption during focal physiologic neural activity. Science 241: 462-464, 1988
30) Fox PT, Raichle ME: Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci U S A 83: 1140-1144, 1986
31) Prichard J, Rothman D, Novotny E, Petroff O, Kuwabara T, et al: Lactate rise detected by 1H NMR in human visual cortex during physiologic stimulation. Proc Natl Acad Sci U S A 88: 5829-5831, 1991
32) Pellerin L, Magistretti PJ: Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91: 10625-10629, 1994
33) Pellerin L, Magistretti PJ: Food for thought: challenging the dogmas. J Cereb Blood Flow Metab 23: 1282-1286, 2003
34) Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, et al: Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia 55: 1251-1262, 2007
35) Jolivet R, Allaman I, Pellerin L, Magistretti PJ, Weber B: Comment on recent modeling studies of astrocyte-neuron metabolic interactions. J Cereb Blood Flow Metab 30: 1982-1986, 2010
36) Takahashi S, Izawa Y, Suzuki N: Astrogliopathy as a loss of astroglial protective function against glycoxidative stress under hyperglycemia. 臨床神経52: 41-51, 2012
37) Takahashi S, Izawa Y, Suzuki N: Astroglial pentose phosphate pathway rates in response to high-glucose environments. ASN Neuro 2012 Mar 22; 4(2). pii: e00078．doi: 10.1042/AN20120002
38) Buckner RL, Vincent JL: Unrest at rest: default activity and spontaneous network correlations. Neuroimage 37: 1091-1096, 2007
39) Buckner RL, Andrews-Hanna JR, Schacter DL: The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci 1124: 1-38, 2008
40) Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, et al: Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition. Proc Natl Acad Sci U S A 107: 17763-17767, 2010
41) Hardy JA, Higgins GA: Alzheimer's disease: the amyloid cascade hypothesis. Science 256: 184-185, 1992
42) Sochocka M, Koutsouraki ES, Gsiorowski K, Leszek J: Vascular oxidative stress and mitochondrial failure in the pathobiology of Alzheimer's disease: new approach to therapy. CNS Neurol Disord Drug Targets 12: 870-871, 2013
43) Leuner K, Müller WE, Reichert AS: From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer's disease. Mol Neurobiol 46: 186-193, 2012
44) Zhang DX, Gutterman DD: Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292: H2023-2031, 2007
45) Cummings JL, Vinters HV, Cole GM, Khachaturian ZS: Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology 51(1 Suppl 1): S2-17, 1998
46) Chan CS, Gertler TS, Surmeier DJ: Calcium homeostasis, selective vulnerability and Parkinson's disease. Trends Neurosci 32: 249-256, 2009
47) Greenamyre JT, Hastings TG: Parkinson's: divergent causes, convergent mechanisms. Science 304: 1120-1122, 2004
48) Miyazaki I, Asanuma M: Approaches to prevent dopamine quinone-induced neurotoxicity. Neurochem Res 34: 698-706, 2009
49) Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H: NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol 99: 14-20, 2000
50) Hishikawa N, Hashizume Y, Yoshida M, Sobue G: Widespread occurrence of argyrophilic glial inclusions in Parkinson's disease. Neuropathol Appl Neurobiol 27: 362-372, 2001
51) Braak H, Sastre M, Del Tredici K: Development of alpha-synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathol 114: 231-241, 2007
52) Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM: α-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62: 9-14, 2000
53) Tanji K, Imaizumi T, Yoshida H, Mori F, Yoshimoto M, et al: Expression of alpha-synuclein in a human glioma cell line and its up-regulation by interleukin-1beta. Neuroreport 12: 1909-1912, 2001
54) Mori F, Tanji K, Yoshimoto M, Takahashi H, Wakabayashi K: Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Exp Neurol 176: 98-104, 2002
55) Goedert M, Clavaguera F, Tolnay M: The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33: 317-325, 2010
56) Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, et al: Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24: 197-211, 2003
57) Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ, et al: Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209: 975-986, 2012
58) de Castro IP, Martins LM, Loh SH: Mitochondrial quality control and Parkinson's disease: a pathway unfolds. Mol Neurobiol 43: 80-86, 2011
59) Mildaziene V, Nauciene Z, Krab K: The targets of 2,2∥,5,5∥-tetrachlorobiphenyl in the respiratory chain of rat liver mitochondria revealed by modular kinetic analysis. Mol Biol Rep 29: 31-34, 2002
60) Okamoto K, Kondo-Okamoto N, Ohsumi Y: Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell 17: 87-97, 2009
61) Houten SM, Auwerx J: PGC-1alpha: turbocharging mitochondria. Cell 119: 5-7, 2004
62) Mortiboys H, Johansen KK, Aasly JO, Bandmann O: Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2．Neurology 75: 2017-2020, 2010
63) Ng CH, Mok SZ, Koh C, Ouyang X, Fivaz ML, et al: Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci 29: 11257-11262, 2009
64) Dagda RK, Chu CT: Mitochondrial quality control: insights on how Parkinson's disease related genes PINK1, parkin, and Omi/HtrA2 interact to maintain mitochondrial homeostasis. J Bioenerg Biomembr 41: 473-479, 2009
65) Halliday GM, Stevens CH: Glia: initiators and progressors of pathology in Parkinson's disease. Mov Disord 26: 6-17, 2011
66) Hirsch EC: Glial cells and Parkinson's disease. J Neurol 247(Suppl 2): II58-62, 2000
67) Wheeler DD, Edwards AM, Chapman BM, Ondo JG: A model of the sodium dependence of dopamine uptake in rat striatal synaptosomes. Neurochem Res 18: 927-936, 1993
68) Torres GE, Gainetdinov RR, Caron MG: Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4: 13-25, 2003
69) Semenoff D, Kimelberg HK: Autoradiography of high affinity uptake of catecholamines by primary astrocyte cultures. Brain Res 348: 125-136, 1985
70) Savchenko VL, McKanna JA, Nikonenko IR, Skibo GG: Microglia and astrocytes in the adult rat brain: comparative immunocytochemical analysis demonstrates the efficacy of lipocortin 1 immunoreactivity. Neuroscience 96: 195-203, 2000
71) Mythri RB, Venkateshappa C, Harish G, Mahadevan A, Muthane UB, et al: Evaluation of markers of oxidative stress, antioxidant function and astrocytic proliferation in the striatum and frontal cortex of Parkinson's disease brains. Neurochem Res 36: 1452-1463, 2011
72) Dringen R, Pfeiffer B, Hamprecht B: Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. J Neurosci 19: 562-569, 1999
73) Lu SC: Regulation of glutathione synthesis. Mol Aspects Med 30: 42-59, 2009
74) 髙橋愼一: アストロサイトと糖代謝. Clin Neurosci 29: 1262-1267, 2011
75) Takahashi S, Izawa Y, Suzuki N: Necessity of glucose for the activation of pentose phosphate pathway in astroglia under hypoxic conditions. Abstract Society for Neuroscience Program 2011: #11.11．(abstr). 2011
76) Takahashi S: Astroglial protective mechanisms against ROS under brain ischemia. 臨床神経51: 1032-1035, 2011
77) Vargas MR, Johnson JA: The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med. 2009; 11: e17．doi: 10.1017/S1462399409001094
78) Venkateshappa C, Harish G, Mythri RB, Mahadevan A, Bharath MM, et al: Increased oxidative damage and decreased antioxidant function in aging human substantia nigra compared to striatum: implications for Parkinson's disease. Neurochem Res 37: 358-369, 2012
79) Chinta SJ, Kumar MJ, Hsu M, Rajagopalan S, Kaur D, et al: Inducible alterations of glutathione levels in adult dopaminergic midbrain neurons result in nigrostriatal degeneration. J Neurosci 27: 13997-14006, 2007
80) Asanuma M, Miyazaki I, Diaz-Corrales FJ, Kimoto N, Kikkawa Y, et al: Neuroprotective effects of zonisamide target astrocyte. Ann Neurol 67: 239-249, 2010
81) Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, et al: Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases. J Neuropathol Exp Neurol 72: 18-28, 2013
82) Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 414: 13-20, 2001
83) Brownlee M: The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54: 1615-1625, 2005
84) Abe T, Takahashi S, Suzuki N: Oxidative metabolism in cultured rat astroglia: effects of reducing the glucose concentration in the culture medium and of D-aspartate or potassium stimulation. J Cereb Blood Flow Metab 26: 153-160, 2006
85) Takahashi S, Abe T, Izawa Y, Suzuki N: Effects of fluctuating glucose concentrations on oxidative metabolism of glucose in cultured neurons and astroglia. Journal of Diabetes Mellitus 2: 19-26, 2012
86) Izawa Y, Takahashi S, Suzuki N: Pioglitazone enhances pyruvate and lactate oxidation in cultured neurons but not in cultured astroglia. Brain Res 1305: 64-73, 2009
87) Colla E, Jensen PH, Pletnikova O, Troncoso JC, Glabe C, et al: Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J Neurosci 32: 3301-3305, 2012
88) Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, et al: Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J Neurosci 32: 3306-3320, 2012
89) Palacios N, Gao X, McCullough ML, Jacobs EJ, Patel AV, et al: Obesity, diabetes, and risk of Parkinson's disease. Mov Disord 26: 2253-2259, 2011
90) Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, et al: Diabetes and risk of Parkinson's disease. Diabetes Care 34: 910-915, 2011
91) Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B: Diabetes and the risk of developing Parkinson's disease in Denmark. Diabetes Care 34: 1102-1108, 2011
92) Trinh K, Moore K, Wes PD, Muchowski PJ, Dey J, et al: Induction of the phase II detoxification pathway suppresses neuron loss in Drosophila models of Parkinson's disease. J Neurosci 28: 465-472, 2008
93) Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, et al: Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: critical role for the astrocyte. Proc Natl Acad Sci U S A 106: 2933-2938, 2009
94) Lastres-Becker I, Ulusoy A, Innamorato NG, Sahin G, Rábano A, et al: α-Synuclein expression and Nrf2 deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Hum Mol Genet 21: 3173-3192, 2012
95) Cook AL, Vitale AM, Ravishankar S, Matigian N, Sutherland GT, et al: NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson's disease. PLoS One 6: e21907, 2011．doi: 10.1371/journal.pone.0021907
96) Im JY, Lee KW, Woo JM, Junn E, Mouradian MM: DJ-1 induces thioredoxin 1 expression through the Nrf2 pathway. Hum Mol Genet 21: 3013-3024, 2012
97) Lin SX, Lisi L, Dello Russo C, Polak PE, Sharp A, et al: The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1．ASN Neuro. 2011; 3(2). pii: e00055．doi: 10.1042/AN20100033
98) Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, et al: Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 341: 274-284, 2012
99) Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, et al; CONFIRM Study Investigators: Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367: 1087-1097, 2012
100) Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, et al; DEFINE Study Investigators: Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367: 1098-1107, 2012
掲載誌情報
