2004 Fiscal Year Final Research Report Summary
Mutational and functional analysis for Familial Parkinson's disease
| Project/Area Number |
15390277
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | JUNTENDO UNIVERSITY |
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Principal Investigator |
HATTORI Nobutaka Juntendo Medical, Associate Professor, 医学部, 助教授 (80218510)
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| Co-Investigator(Kenkyū-buntansha) |
SATO Kenichi Juntendo Medical, Assistant, 医学部, 助手 (00276461)
MIZUNO Yoshikuni Juntendo Medical, Professor, 医学部, 教授 (30049043)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Familial Parkinson's disease / parkin gene / PINK1 gene / DJ-1 gene / dopainine quinone / ligase activities / 14-3-3η / Knock-down parkin |
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| Research Abstract |
Parkinson's disease (PD) is the second most common neurodegenerative disorder with a prevalence of 1% in individuals older than 65 years of age. Although the majority of PD cases are sporadic, it is now clear that genetic factors contribute to the pathogenesis of PD. In the present study, we found several mutations in PINK1, responsible for PARK6. Approximately <9% among the patients with recessive mode of inheritance. Furthermore, another causative gene, DJ-1 has been identified as a causative gene for PARK7. However, we did not find out DJ-1 mutations. Taken together with parkin gene mutations analysis, approximately 40% of the patients we studied had no mutations in the reported genes. Thus, we believed that a novel mutation in unknown genes could be present. Now we continue to perform the linkage study for identification of a novel gene. In contrast, functional analysis for the gene products could provide us good information for elucidating the mechanism of not only monogenic PD but also sporadic PD. In the present study, we found a common pathway between a-synuclein and parkin such as dopamine metabolisms. We could establish the in vitro assay knock-down parkin using antisense parkin strand. Knock-down parkin induced the increasing of dopamine chrome derived from dopamine quinone. Interestingly, the increasing was inhibited by expression of a-synuclein. In addition, 14-3-3ηthat is one of parkin interaqctive molecules inhibited parkin ligase activities. This system was recovered by expression of a-synuclein. In conclusions, gene products for PARK1 and PARK2 shared common pathways. The findings also indicate that all the gene products share common pathways in the pathogenesis of nigral degeneration.
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