2007 Fiscal Year Final Research Report Summary
Parkinson's disease modeling by systemic proteasome ibhibition in mice
| Project/Area Number |
17590889
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Wakayama Medical University |
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Principal Investigator |
MIWA Hideto Wakayama Medical University, Department of Neurology, Associate Professor (50231626)
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| Co-Investigator(Kenkyū-buntansha) |
KONDO Tomoyoshi Wakayama Medical University, Department of Neurology, Professor (50103891)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Proteasome / Mice / substantia nigra / Dopamine |
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| Research Abstract |
Parkinson's disease (PD) is one of the most frequent neurodegenerative disorders. Neuropathologically, PD is characterized by degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc) and the presence of alpha-synuclein-immunopositive Lewy bodies. Currently, the exact etiopathogenic mechanisms underlying the neuron degeneration in PD remains uncertain; however, one key to understanding of them may be the ubiquitin-proteasome protein degradation system, since proteins coded by genes whose mutations have been identified as the cause of familial PD have been suggested to affect the function of ubiquitin-proteasome system (UPS), directly or indirectly. In addition, alpha-synuclein is a substrate to be degraded by UPS, and mutant alpha-synuclein cannot be degraded by UPS. There is an emerging hypothesis that failure of UPS and subsequently induced protelytic stress may contribute to neuron degeneration in PD (McNaught and Olanow, 2003). However, there has been controvers
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y on the reproduceability of PD modeling by proteasome inhibition in animals. Although the PD modeling by proteasome inhibition is theoretically appealing, further accumulation of experimental findings is necessary to validate its significance. Thus, the present study aims to examine the effect of systemic administration of proteasome inhibitor in mice, particularly to confirm whether or not the nigrostriatal dopaminergic neurons are damaged.
Following systemic injection of PSI (5 mg/kg, 6 times/2 weeks), a potent inhibitor of proteasome, mice showed a transient hypokinetic state. After suvivinv period of 4 weeks, PSI-treated mice were sacrificed. Stereologicl quantification of substantia nigra showed that number of tyrosine hydrokylase-immunohipositive dopamine neurons did not decrease. Alpha-synuclein immunohistochemistry showed no inclusions in dopamine neurons. In addition, no microglial activation was demonstrated in either substantia nigra or striatum. Based on those findings, it is suggested that systemic porteasome inhibition could not damage nigro-striatal dopamine neurons in mice. Less
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Research Products
(8 results)
