2002 Fiscal Year Final Research Report Summary
Clinical and basic investigation on the pathogenesis of multiple system atrophy
| Project/Area Number |
13670666
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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 | Keio University |
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Principal Investigator |
HAMADA Junichi Keio University, School of Medicine, assistant professor, 医学部, 専任講師 (70180940)
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| Co-Investigator(Kenkyū-buntansha) |
GOTOH Kyoko Keio University, School of Medicine, assistant, 医学部, 助手 (90317107)
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| Project Period (FY) |
2001 – 2002
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| Keywords | multiple system atrophy / corticobasal degeneration / heat shock ploteins / tau / cyclin-dependent kinare / p38 MAP kinase / caspase / endoplasmic reticulum stress |
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| Research Abstract |
Although we did not have any opportunity to experience an autopsied case of multiple system atrophy (MSA) during the designated term, we had an autopsied case of corticobasal degeneration (CBD). We performed histological analysis on this case. We found that there was increased occurrence of DNA fragmentation revealed by the TUNEL method in the frontal lobe that had exhibited marked atrophy on MRI performed before the patient's death. The TUNEL-positive cells were identified as neurons and glial cells by double immunostaining. In comparison, we observed only a small number of TUNEL-positive cells in the occipital lobe, which is generally spared in CBD. In ballooned neurons, there was increased immunoreactivity for αB crystallin, a member of small heat shock proteins. Moreover, double immunostaining showed that phosphorylated tau in neurofibrillary tangles, astrocytoc plaques, and coiled bodies co-localized with immunoreactivity for cyclin-dependent kinase 5 and phosphorylated (activated) p38, implying that these kinases are responsible for aberrant phosphorylation of tau in these abnormal neuronal and glial inclusions. It is obvious that systematic analysis of cell death-related pathways is indispensable to investigate the pathogenesis of neurodegenerative diseases including MSA. Therefore, we thoroughly explored mitochondtia- and endoplasmic reticulum-related cell death pathways in permanent ischemia and ischemia/reperfusion models in mice. It was revealed that ischemia leads to rapid degradation of dynein, which resulted in the liberation of Bim, a BH3-only protein, from this motor protein complex. Subsequently, Bim is recruited to mitochondria, which then induced cytochrome c release and caspase-9 activation. In an ischemia/reperfusion model, our study disclosed that the activation of caspase-12 occurs in the wake of ER stress.
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Research Products
(6 results)
