| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥900,000 (Direct Cost: ¥900,000)
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| Research Abstract |
We have found a novel component of Aizheimer's disease (AD) amyloid, named NAG (non-Abeta component of AD 'amyloid) and cloned the cDNA encoding NAG precursor protein, NACP. NACP is now known as human aipha-synuclein. We have shown that aipha-synuclein is aberrantly expressed not only in synaptic regions, but also In dystrophic neurites in AD brains. Recently, missense mutations In the alpha-synuclein gene were found in familial Parkinson's disease (PD) pedigrees In an autosomal dominant fashion and were shown to segregate with the illness. We have shown that entire molecule of aipha-synuclein constitutes filamentous components of Lewy bodies, a neuropathologlcal hallmark of PD and of dementia with Lewy bodies (DLB), and cytopiasmic inclusions of multiple system atrophy (MSA). It has been shown that recombinant aipha-synuclein forms fibrils in vitro like Lewy bodies and that the fibril formation Is accelerated with those mutations.
Thus, aipha-synuclein is a common pathogenic molecule In these degenerative diseases, and it seems that the accumulation of abnormal structures of aipha-synuclein within neurons, axons, dendrites, and presynaptic regions interfere the function of neuron, I.e., neurotransmlssion, leading to Parkinsonism and dementia as symptoms, and eventually to neuronal cell death. We have shown that the NAG region of aipha-synuclein, which is shown to be important for fibrillogenesis, is hard to digest by some protelnases. We also have revealed that tubulin is an alpha-synuclein-binding protein and that tubulin seeds aipha-synuclein fibril formation. We have cloned the gene for human aipha-synuclein and revealed the genomic structure of this gene, and found that there are polymorphisms in the promoter region and in an exon of aipha-synuclein gene.
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