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ニホンザル 餌を得るため2匹が協力 初めて確認か 阪大が実験 (NHK)

2匹のニホンザルが餌を獲得するために互いに協力して行動できることを大阪大学の研究グループが実験で確認し、ニホンザルの新たな側面として注目されています。 実験を進...

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GBA haploinsufficiency accelerates alpha synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease=.

著者 Ikuno M , Yamakado H , Akiyama H , Parajuli LK , Taguchi K , Hara J , Uemura N , Hatanaka Y , Higaki K , Ohno K , Tanaka M , Koike M , Hirabayashi Y , Takahashi R
Hum Mol Genet.2019 Jan 28 ; ():.
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Parkinson's disease (PD) is characterized by dopaminergic cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only double-mutant mice showed a significant reduction in dopaminergic cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Double-mutant mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while double-mutant mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo.
PMID: 30689867 [PubMed - as supplied by publisher]
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