Reducing toxicity of disease-causative molecules with the aim of developing therapies for neurodegenarative diseases
| Project/Area Number |
19K07970
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
豊田 知子 産業医科大学, 医学部, 助教 (30596432)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ポリグルタミン病 / 球脊髄性筋萎縮症 / 歯状核赤核淡蒼球ルイ体萎縮症 / HIKESHI / 凝集体形成抑制 / 分子シャペロン / 毒性軽減 |
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| Outline of Research at the Start |
本研究では、SBMA、DRPLA、HD、SCA1のモデルを用いて、分子シャペロンの活性化や翻訳後修飾による病因蛋白質に特異性の高い強力な治療法を開発するために、HIKESHIの高発現、AR、atrophin-1、huntingtin、ataxin-1の各種化合物による治療効果を検討する。次に、各疾患の剖検組織やマウスモデルでHIKESHIの発現量操作による効果を検討して、蛋白質分解系の神経変性疾患の病態形成への関与を生化学的・免疫組織化学的に調べる。これらにより、各疾患での病因蛋白質除去に関しての特異的な病態を明らかにし、分子シャペロン誘導あるいは凝集体形成抑制による治療法を開発する。
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| Outline of Final Research Achievements |
In chronic neurodegenerative diseases such as polyglutamine (polyQ), commonly observed phenotypes include the abnormal accumulation of disease-causing proteins and the formation of nuclear and cytoplasmic inclusions. We examined the effects of HIKESHI overexpression in cultured cell models of neurodegenerative diseases. HIKESHI overexpression preferentially decreased the expression of mutant atrophin-1 in the neuronal cell models. HIKESHI overexpression also demonstrated the therapeutic effects in the transgenic mouse model of dentatorubral-pallidoluysian atrophy. These findings demonstrated that HIKESHI enhanced the preferential degradation of the disease-causative proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、代表的な神経変性疾患であるポリグルタミン病の病態を明らかにし、有効な病態抑止治療を開発することを目的とした。分子シャペロンを核内へ運搬する役割を果たすHIKESHIは熱ストレスに対する細胞の防御機構を増強して細胞死を抑制するが、実際に、HIKESHIの高発現による分子シャペロンの細胞内発現分布の変動や部位特異的なシャペロン機能の増強が神経変性疾患の病態の改善につながることを本研究によって見いだした。これらの調節因子の誘導による病因蛋白質を選択的に強力に分解する治療法を開発することは、従来にない神経変性疾患の治療や予防法として新たな展開になると考えられる。
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Report
(4 results)
Research Products
(32 results)
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[Journal Article] Complete sequencing of expanded SAMD12 repeats by long-read sequencing with Cas9-mediated enrichment.2021
Author(s)
Mizuguchi T, Toyota T, Miyatake S, Mitsuhashi S, Doi H, Kudo Y, Kishida H, Hayashi N, Tusburaya RS, Kinoshita M, Fukuyama T, Fukuda H, Koshimizu E, Tsuchida N, Uchiyama Y, Fujita A, Takata A, Miyake N, Kato M, Tanaka F, Adachi H, Matsumoto N.
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Journal Title
Brain
Volume: 144
Issue: 4
Pages: 1103-1117
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Eating Disorder Neuroimaging Initiative (EDNI): a multicentre prospective cohort study protocol for elucidating the neural effects of cognitive?behavioural therapy for eating disorders2021
Author(s)
Hamatani S, Hirano Y, Sugawara A, Isobe M, Kodama N, Yoshihara K, Moriguchi Y, Ando T, Endo Y, Takahashi J, Nohara N, Takamura T, Hori H, Noda T, Tose K, Watanabe K, Adachi H, Gondo M, Takakura S, Fukudo S, Shimizu E, Yoshiuchi K, Sato Y, Sekiguchi A.
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Journal Title
BMJ Open
Volume: 11
Issue: 1
Pages: e042685-e042685
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Olfactory-cognitive index distinguishes involvement of frontal lobe shrinkage, as in sarcopenia from shrinkage of medial temporal areas, and global brain, as in Kihon Checklist frailty/dependence, in older adults with progression of normal cognition to Alzheimer's disease.2021
Author(s)
Iritani O, Okuno T, Miwa T, Makizako H, Okutani F, Kashibayashi T, Suzuki K, Hara H, Mori E, Omoto S, Suzuki H, Shibata M, Adachi H, Kondo K, Umeda-Kameyama Y, Kodera K, Morimoto S.
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Journal Title
Geriatr Gerontol Int
Volume: 21
Issue: 3
Pages: 291-298
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.2020
Author(s)
Minakawa EN, Popiel HA, Tada M, Takahashi T, Yamane H, Saitoh Y, Takahashi Y, Ozawa D, Takeda A, Takeuchi T, Okamoto Y, Yamamoto K, Suzuki M, Fujita H, Ito C, Yagihara H, Saito Y, Watase K, Adachi H, Katsuno M, Mochizuki H, Shiraki K, Sobue G, Toda T, Wada K, Onodera O, Nagai Y.
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Journal Title
Brain
Volume: 143
Issue: 6
Pages: 1811-1825
DOI
Related Report
Peer Reviewed
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[Journal Article] DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes52019
Author(s)
Kondo N, Tohnai G, Sahashi K, Iida M, Kataoka M, Nakatsuji H, Tsutsumi Y, Hashizume A, Adachi H, Koike H, Shinjo K, Kondo Y, Sobue G, Katsuno M.
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Journal Title
EMBO Mol Med
Volume: none
Issue: 5
DOI
Related Report
Peer Reviewed / Open Access
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[Book] 今日の治療指針2020
Author(s)
足立弘明
Total Pages
2192
Publisher
医学書院
ISBN
4260039407
Related Report
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[Book] 今日の診断指針2020
Author(s)
足立弘明
Total Pages
2079
Publisher
医学書院
ISBN
4260038087
Related Report
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