2004 Fiscal Year Final Research Report Summary
Pathological study of mutant SOD1 (G93A and H46R) transgenic mice
| Project/Area Number |
14570623
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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 | Tokyo Women's Medical University |
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Principal Investigator |
SASAKI Shoichi Tokyo Women's Medical University, Neurological Institute, Neurology, Associate Professor, 医学部, 助教授 (40119962)
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| Project Period (FY) |
2002 – 2004
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| Keywords | amyotrophic lateral sclerosis / SOD1 / mutant SOD1 transgenic mice / axonal transport / mitochondria / aggregate / electron microscopy / immuno-electron microscopy |
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| Research Abstract |
We electronmicroscopically and immunoelectronmicroscopically investigated the spinal cords of transgenic(Tg) mice with a G93A mutant SOD1 gene to elucidate the pathomechanisms of this animal model for familial ALS.
(1)Proximal axons directly emanating from normal-looking anterior horn cells with increased neurofilaments or, to a lesser extent, increased mitochondria, were more frequently observed in Tg mice than in the controls, even at the early presymptomatic stage, and the frequency increased with time. The somata of motor neurons directly connected with proximal axons did not exhibit any abnormal accumulation of neurofilaments or mitochondria.
(2)Vacuoles of various sizes were observed in the anterior root exit zone, anterior root, and in the neuropils of the anterior horn. The intermembrane space of mitochondria was frequently vacuolated. In mitochodria with advanced vacuolation, the vacuolar space was filled with a granular or amorphous substance. Both SOD1 and ubiquitin determinants were localized in vacuolated mitochondria. The vacuolated mitochondria were exclusively observed in the axons, and not in proximal dendrites or somata.
(3)SOD1-and ubiquitin-positive aggregates and Lewy body-like inclusions were frequently demonstrated in the neuronal processes including cord-like swollen axons and in some remaining anterior horn neurons in Tg mice. The aggregates increased in size and frequency with time. The aggregates almost always consisted basically of interwoven intermediate filaments (about 10-15 nm in diameter), showing a high level of human SOD1-and ubiquitin-immunogold labeling. Aggregates were frequently shown, predominating in the neuronal processes of the anterior horns including the proximal axons, whereas they were rather rare in the somata and dendrites.
Thus, impairment of proximal axonal transport may play a pivotal role in the pathomechanism of this model.
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