Novel function of sigma-1 receptor and therapeutics strategy for neurodegenerative disorders
Project/Area Number |
24659024
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Single-year Grants |
Research Field |
Biological pharmacy
|
Research Institution | Tohoku University |
Principal Investigator |
FUKUNAGA KOHJI 東北大学, 薬学研究科(研究院), 教授 (90136721)
|
Co-Investigator(Kenkyū-buntansha) |
SHIODA Norifumi 東北大学, 大学院薬学研究科, 助教 (00374950)
|
Project Period (FY) |
2012-04-01 – 2014-03-31
|
Project Status |
Completed (Fiscal Year 2013)
|
Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
|
Keywords | 筋萎縮性側索硬化症 / シグマー1受容体 / ミトコンドリア障害 / 小胞体ストレス / メチルピルビン酸 / ALS治療薬 / 筋萎縮側索硬化症 / sigma-1 受容体 / TDP-43 / TCA 回路 / ピルビン酸 / Sigma-1受容体 / IP3 受容体 / 脳血管性認知症 / 抗うつ薬 |
Research Abstract |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motor neuron dysfunction. Recently, a E102Q mutation in the chaperone protein sigma-1 receptor (R) was discovered in familial ALS patients. Here, we address mechanisms underlying neurodegeneration caused by this mutation using overexpression analysis in neuro2A cells. Sigma-1R(E102Q) overexpression promoted its dissociation from the endoplasmic reticulum (ER) membrane and its cytoplasmic aggregation, and in turn impaired mitochondrial ATP production. Under ER stress condition, sigma-1R(E102Q) overexpression aggravated mitochondrial damage, thereby causing apoptosis. The enhancement of ATP production by methyl pyruvate treatment rescued mitochondrial damage induced by sigma-1R(E102Q) overexpression. Taken together, phenotypes observed in sigma-1R(E102Q)-overexpressing cells suggest that ATP supplementation by methyl pyruvate is potential therapeutic strategy to treat ALS caused by sigma-1R mutations.
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Report
(3 results)
Research Products
(124 results)
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[Journal Article] Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo2014
Author(s)
Tao RR, Wang H, Hong LJ, Huang JY, Lu YM, Liao MH, Ye WF, Lu NN, Zhu DY, Huang Q, Fukunaga K, Lou YJ, Shoji I, Wilcox CS, Lai EY, Han F
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Journal Title
Antioxid Redox Signal
Volume: (in press)
Issue: 1
Pages: 1-16
DOI
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Peer Reviewed / Open Access
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[Journal Article] Melatonin reverses the decreases in hippocampal protein serine/threonine kinases observed in an animal model of autism2014
Author(s)
Tian Y, Yabuki Y, Moriguchi S, Fukunaga K, Mao PJ, Hong LJ, Lu YM, Wang R, Ahmed MM, Liao MH, Huang JY, Zhang RT, Zhou TY, Long S, Han F
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Journal Title
J Pineal Res.
Volume: 56
Issue: 1
Pages: 1-11
DOI
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[Journal Article] Targeted therapy of brain ischaemia using Fas ligand antibody conjugated PEG-lipid nanoparticles2013
Author(s)
Lu YM, Huang JY, Wang H, Lou XF, Liao MH, Hong LJ, Tao RR, Ahmed MM, Shan CL, Wang XL, Fukunaga K, Du YZ, Han F
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Journal Title
Biomaterials
Volume: 35
Issue: 1
Pages: 530-7
DOI
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Peer Reviewed
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[Journal Article] The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain2013
Author(s)
Huang JY, Lu YM, Wang H, Liu J, Liao MH, Hong LJ, Tao RR, Ahmed MM, Liu P, Liu SS, Fukunaga K, Du YZ, Han F
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Journal Title
Biomaterials
Volume: 34
Issue: 32
Pages: 7960-70
DOI
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Peer Reviewed
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[Journal Article] Interaction of PICK1 with C-Terminus of Growth Hormone–Releasing Hormone Receptor (GHRHR) Modulates Trafficking and Signal Transduction of Human GHRHR2013
Author(s)
Katsushima Y, Sato T., Yamada C., Ito M., Suzuki Y., Ogawa E., Sukegawa I., Sukegawa J., Fukunaga K., Yanagisawa T.
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Journal Title
Journal of Pharmacological Sciences
Volume: 122
Issue: 3
Pages: 193-204
DOI
NAID
ISSN
1347-8613, 1347-8648
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Peer Reviewed
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[Journal Article] Influence of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on socioemotional behaviors in offspring rats.2013
Author(s)
Nguyen AT, Nishijo M, Hori E, Nguyen NM, Pham TT, Fukunaga K, Nakagawa H, Tran AH, Nishijo H.
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Journal Title
Environ Health Insights
Volume: 7
Pages: 1-14
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[Journal Article] The Disturbance of Hippocampal CaMKII/PKA/PKC Phosphorylation in Early Experimental Diabetes Mellitus.2013
Author(s)
Liao MH, Xiang YC, Huang JY, Tao RR, Tian Y, Ye WF, Zhang GS, Lu YM, Ahmed MM, Liu ZR, Fukunaga K, Han F.
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Journal Title
CNS Neurosci Ther.
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Pages: 329-36
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[Journal Article] The γ-secretase blocker DAPT reduces the permeability of the blood-brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia.2013
Author(s)
Zhang GS, Tian Y, Huang JY, Tao RR, Liao MH, Lu YM, Ye WF, Wang R, Fukunaga K, Lou YJ, Han F.
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Journal Title
CNS Neurosci Ther.
Volume: 19(1)
Issue: 1
Pages: 53-60
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[Journal Article] Tao RR, Huang JY, Shao XJ, Ye WF, Tian Y, Liao MH, Fukunaga K, Lou YJ, Han F, Lu YM. Ischemic injury promotes Keap1 nitration and disturbance of antioxidative responses in endothelial cells: a potential vasoprotective effect of melatonin.2013
Author(s)
Tao RR, Huang JY, Shao XJ, Ye WF, Tian Y, Liao MH, Fukunaga K, Lou YJ, Han F, Lu YM.
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Journal Title
J Pineal Res.
Volume: 54(3)
Issue: 3
Pages: 271-281
DOI
Related Report
Peer Reviewed
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