2004 Fiscal Year Final Research Report Summary
MUTATIONAL ANALYSIS OF THE PARKIN GENE AND FUNCTIONAL ANALYSIS OF THE PARKIN PROTEIN
| Project/Area Number |
13210122
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
MIZUNO Yoshikuni JUNTENDO UNIVERSITY, SCHOOL OF MEDICINE, DEPARTMENT OF NEUROLOGY, PROFESSOR, 医学部, 教授 (30049043)
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| Co-Investigator(Kenkyū-buntansha) |
HATTORI Nobutaka JUNTENDO UNIVERSITY, SCHOOL OF MEDICINE, DEPARTMENT OF NEUROLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (80218510)
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| Project Period (FY) |
2001 – 2004
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| Keywords | Parkinson's disease / Parkin / Alpha-synulcein / PINK1 / DJ-1 / LRRK2 / Pathogenesis / Familial Parkinson's disease |
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| Research Abstract |
We investigated mutations in the parkin gene, which had been cloned by our group, in more than 500 families with Parkinsons's disease. We found parkin mutations in approximately 50% of autosomal recessive families. In addition, among parkin-negative families, we found 8 families with PINK] mutations (PARK6), 10 families with LRRK2 mutations (PARK8), and 2 families with duplication of the alpha-synuclein gene (PARK 1). We did not find DJ-1 mutations (PARK7). Regarding the function of Parkin protein, we found that 14-3-3 protein was a regulatory protein for Parkin, in that 14-3-3 was attaching the linger region of Parkin and negatively regulating the enzymatic activity of Parkin as E3 of the ubiquitin system. Upon oxidative stress, alpha-synuclein is upregulated and attaches to 14-3-3; then the conjugate of these two proteins detaches from Parkin releasing the activity of Parkin as E3. We further revealed that parkin knockout SH-SY5Y cells showed increase in dopamine quinone formation in
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ducing oxidative stress. These two observations are consistent with each other indicating a possible mechanism for selective damage of nigral neurons in PARK2, in that neurons not exposed to oxidative stress do not require much of Parkin activity. It has been a question why Parkin-interacting proteins were not accumulated in nigral neurons of PARK2 patients. As an answer for this question, we found an evidence to indicate lysine-63 mediated polyubiquitilation by Parkin. We found that LMO4, a transcription regulatory protein, underwent Lys-63 mediated polyubiqutilationm which did not confer a signal for degradation by 26S proteasome. Lys-63 mediated polyubiquitylated proteins have different biological roles such as DNA repair and endocytosis among others. This observation opens new approaches for the investigation of the pathogenesis of PARK2. Furthermore, we succeeded in the production of hemi-parkinsonism rat model by transfecting alpha-synuclein gene using AAV vector. Co-transfection of parkin partially prevented the loss of nigral neurons in this model. This approach can be extended to gene therapy of human patients with Parkinson's disease. Less
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[Journal Article] Novel PINK 1 mutations in early-onset parkinsonism.2004
Author(s)
Hatano Y, Li Y, Sato K, Asakwa S, Yamamura Y, Tomiyama H, Yoshino H, Asahina M, Kobyshi S, Ng Ar, Rosals RL, Hassin-Bear S, Shinar Y, Lu CS, Shimizu N, Toda T, Mizuno Y, Hattori N.
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Journal Title
Ann Neuro 56
Pages: 424-427
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] PARK6-linked autosomal recessive early-onset parkinsonism In Asian populations.2004
Author(s)
Hatano Y, Sato K, Elibol B, Yoshino H, Yamamura Y, Bonifati V Shinotoh H, Asahina M, Kobayshi S, Ng Ar, RosalesRL, Hassin-Bear S, Shinar Y, Lu CS, Chang HC, Wu Chou Y, Atac FB, Kobayashi T, Toda T, Mizuno Y, Hattori N.
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Journal Title
Neurology 63
Pages: 1482-1485
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology.2003
Author(s)
Kobayashi T, Ota S, Tanaka K, Ito Y, Hasegawa M, Umeda Y, Motoi Y, Takanashi M, Yasuhara M, Anno M, Mizuno Y, Mori H.
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Journal Title
Ann.Neurol. 53
Pages: 133-137
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Haploinsufficiency at the a-synuclein gene underlies phenotypic severity in familial Parkinson's disease.2003
Author(s)
Kobayashi H, Kruger R, Markopoulou K, Wszolek Z, Chase B, Taka H, Mineki R, Murayama K, Riess O, Mizuno Y, Hattori N.
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Journal Title
Brain. 126(Pt 1)
Pages: 32-42
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies.2002
Author(s)
Schossmacher MG, Frosch MP, Ping-Gai W, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Sharon R, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik K.
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Journal Title
Am J Pathol 160
Pages: 1655-1667
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] An AAV-derived apaf-1 dominant negative inhibitor prevents MPTP toxicity as antiapoptotic gene therapy for Parkinson's disease.2001
Author(s)
Mochizuki H, Hayakawa H, Migita M, Shibata M, Tanaka R, Suzuki A, Shimo-Nakanishi Y, Urabe T, Yamada M, Tamayose K, Shimada T, Miura M, Mizuno Y.
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Journal Title
PNAS 98
Pages: 10918-10923
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Developmental changes in the expression of parkin and UbcR7, a parkin-interacting and ubiquitin-conjugating enzyme, in rato brain.2001
Author(s)
Wang M, Suzuki T, Kitada T, Asakawa S, Minoshima S, Shimizu N, Tanaka K, Mizuno Y, Hattori N.
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Journal Title
J Neurochem 77
Pages: 1561-1568
Description
「研究成果報告書概要(欧文)」より
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