| Project/Area Number |
06454277
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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 | Tokyo Medical and Dental University (1996)
University of Tsukuba (1994-1995) |
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Principal Investigator |
MIZUSAWA Hidehiro Tokyo Medical & Dental University, Department of Neurology, Professor, 医学部神経内科, 教授 (30144091)
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| Co-Investigator(Kenkyū-buntansha) |
OHKOSHI Norio Tsukuba University, Department of Neurology, Assistant Professor, 臨床医学系神経内科, 講師 (80203751)
藤田 恒夫 筑波大学, 臨床医学系神経内科, 講師 (30261803)
永田 博司 茨城県立医療大学, 教授 (10198335)
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| Project Period (FY) |
1994 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 1996: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1994: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Keywords | ubiquitin / skein-like inclusion / Lewy body-like hyaline inclusion / Bunina body / round inclusion / neurofilament / lysosome / motor neuron disease / Zn superoxide dismutase / ubiguitin / round inclusion / Lewy小体様 / Zn SOD / NOS / cathepsin D |
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| Research Abstract |
Motor neuron diseases (MNDs) including amyotrophic lateral sclerosis (ALS) have characteristic inclusions such as Lewy body-like hyaline inclusion (LBH), skein-like inclusion (SLI) and Bunina body (BB), although the pathogeneses of MNDs remain unknown. The investigation of the formation pathomechanism of these specific inclusions would provide important clues to elucidate the pathogenesis of MNDs.
SLI was essentially a bundle of filaments slightly thicker than neurofilament. SLIs existed singularly or aggregates variously forming networks of bundles, typical skeins and larger inclusions. Single of a few SLIs often appeared similar to BBs particularly when SLIs are cut crossly or obliquely. However, they were distinct because SLIs were ubiquitin-positive and cystatin C-negative while BBs were ubiquitin-negative and cystatin C-positive. Large "SLIs" composed of many bundles usually contained many free filaments associated with granular material which were reminiscent of granule-associated
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thick filaments of round inclusions in sporadic ALS.SLI were negative for neurofilament and Cu/Zu SOD.By ubiquitin immunocytochemistry, SLIs were found in most cases on spradic ALS while similar inclusions were rarely reported in other diseases. Therefore, SLIs have diagnontic value for sporadic ALS.Ultrastructurally some SLIs were observed within double membrane structure probably lysosomes although cathepsin D immunoreactivity of SLIs were not outstanding from cytoplasmic immunoreaction. SLIs were almost negative for ubiquitin C terminal hydrolase or proteasome indicating that ubiquitin system involved in SLI metabolism might be defective and lysosomal system might be also involved.
LBHI which was observed in most cases of familial ALS with posterior column degeneration contains neurofilament particularly in the halo while there were also thicker filaments with granular material. They were often round and occasionally cord-like in shape with quite homogeneous content and smooth outline. LBHI was immunocytochemically positive for Cu/Zn SOD and mutations of Cu/Zn SOD gene were found in this type of familial ALS.LBHI may be related to oxydant stress which is possibly a pathomechanism of MND.
In rare occasions, round inclusion (RI) similar to LBHI was found in sporadic ALS,particularly in cases with rapid clinical course. RIs were composed mainly of thick filaments with granular material. Hematoxylin and eosin staining as well as ubiqitin immunohistochemistry showed RIs were irregular in shape and inhomogeneous or filamentous in content even if they appeared to have distinct core and halo. RIs were usually not immunoreactive for neurofilament of Cu/Zn SOD.RI often contained bundles of thick filaments which were indistinguishable from SLI.These findings indicate that RI is distinct from LBHI but closely related to so-called large aggregated form of SLI. Less
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