2005 Fiscal Year Final Research Report Summary
The specific effect of gene to tau pathology of human brain
| Project/Area Number |
16390323
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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 |
Psychiatric science
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| Research Institution | Kobe University |
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Principal Investigator |
YASUDA Minoru Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 講師 (50359866)
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| Co-Investigator(Kenkyū-buntansha) |
MAEDA Kiyoshi Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80116251)
KAWAMATA Toshio Kobe University, School of Medicine, Professor, 医学部, 教授 (70214690)
YAMAMOTO Yasuji Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (00324921)
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| Project Period (FY) |
2004 – 2005
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| Keywords | frontotemporal dementia / mutation / haplotype / tau / MAPT |
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| Research Abstract |
Mutations in the tau gene (MAPT) cause familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We have found three kinds of MAPT mutations, one of which was an intronic mutation located close to the splice-donor site at position +12 of the intron following exon 10 (+12 mutation), and the other two were missense mutations, N279K and P301S, in exon 10 of the MAPT. Clinical variability is seen not only among families with different mutations but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia-parkinsonism family associated with the P301S mutation. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and preceded dementia. Three autopsied patients shared involvement predominantly in the frontal and temporal lobes, and also in the subcortical nuclei, including substantia nigra, globus pallidus and s
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ubthalamic nucleus that microscopically consisted of neuronal loss, microvacuolation and astrocytic fibrosis. Immunobistochemistry demonstrated neurophil threads, ballooned cells and glial fibrillary tangles. These findings suggest that the MAPTP301S mutation can give rise to pathologically subcortical-predominant neurophil thread-rich tau-containing lesions, which could result in consistent parkinsonism as well as frontal dementia. Our study confirms the notion that the phenotype observed in affected individuals from P301S mutation families is heterogeneous, and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations. Furthermore, we investigated the relationship between the MAPT genotype and clinical features in four MAPT mutations (P301L, +16, N279K and P301S) present in FTDP-17 patients. Our results suggest that MAPT genotype does not influence the age at symptomatic onset or disease duration. However, the MAPT genotype may predispose to a specific clinical presentation in the early disease stage of FTDP-17. Less
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