Therapeutics for polyglutamine diseases through protein degradation pathway: Targeting the nucleus
| Project/Area Number |
24390220
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Partial Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Iwata Atsushi 東京大学, 医学部附属病院, 講師 (40401038)
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| Project Period (FY) |
2012-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2014: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2012: ¥8,710,000 (Direct Cost: ¥6,700,000、Indirect Cost: ¥2,010,000)
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| Keywords | polyglutamine / ubiquitin proteasome / HDAC3 / UHRF2 / ポリグルタミン / ユビキチンリガーゼ / ユビキチン・プロテアソーム / ユビキチン / 細胞核 / タンパク質品質管理 / HDAC / DNAメチル化 |
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| Outline of Final Research Achievements |
Polyglutamine diseases are caused by cytosine-adenine-guanine (CAG) trinucleotide expansions that are translated to a polyglutamine (pQ) chain in specific genes. This pQ chains tend to destabilize the entire proteins making them aggregate. The aggregates are especially toxic in the nucleus for a variety of reasons. Thus, for treating pQ diseases, targeting the nuclear pQ aggregates for degradation seems to be a promising approach. The nuclear ubiquitin proteasome system is the only major protein degradation machinery in the nucleus since the autophagy lysosome system, cannot function in the nucleus. We found that ubiquitin ligase UHRF2 recognizes and promotes nuclear pQ degradation, thus activation of these ubiquitin ligases could be one of the therapeutic approaches. In addition, we also found that one of the histone deacetylases (HDAC), HDAC3, regulates the nuclear ubiquitin proteasome system.
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Report
(5 results)
Research Products
(32 results)
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[Journal Article] Imaging Characteristics and Safety of Florbetapir (18F) in Japanese Healthy Volunteers, Patients with Mild Cognitive Impairment and Patients with Alzheimer's Disease2015
Author(s)
Chihiro Namiki, Yasushi Takita, Atsushi Iwata, Toshimitsu Momose, Michio Senda, Yoshiro Okubo, Abhinay D Joshi, Ming Lu, Christopher Breault, Michael J. Pontecorvo
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Journal Title
Annals of Nuclear Medicine
Volume: 29
Issue: 7
Pages: 570-581
DOI
Related Report
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Familial amyotrophic lateral sclerosis with novel A4D SODl mutation with late age at onset and rapid progressive course.2013
Author(s)
Hiroya Naruse, Atsushi Iwata. Yuji Takahashi, Kazuaki Ichihara, Satoshi Kamei, Masato Yamatoku, Toshikazu Hirayama, Naoki Suzuki, Masashi Aoki, Toji Miyagawa, Jun Shimizu, Shoji Tsuji, Jun Goto
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Journal Title
Neurology and Clinical Neuroscience
Volume: 1
Issue: 1
Pages: 45-47
DOI
Related Report
Peer Reviewed
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[Journal Article] CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy.2012
Author(s)
Mitsui J, Matsukawa T, Ishiura H, Higasa K, Yoshimura J, Saito TL, Ahsan B, Takahashi Y, Goto J, Iwata A, Niimi Y, Riku Y, Goto Y, Mano K, Yoshida M, Morishita S, Tsuji S.
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Journal Title
Am J Med Genet B Neuropsychiatr Genet.
Volume: 159B(8)
Issue: 8
Pages: 951-7
DOI
Related Report
Peer Reviewed
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[Presentation] Altered CpG methylation in Alzheimer’s disease is associated with APP and MAPT dysregulation.2013
Author(s)
Atsushi Iwata, Kenichi Nagata, Hiroyuki Hatsuta, Hiroshi Takuma, Miki Bundo, Kazuya Iwamoto, Akira Tamaoka, Shigeo Murayama, Takaomi Saido, Shoji Tsuji
Organizer
Society for Neuroscience
Place of Presentation
San Diego, CA, USA
Related Report
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