https://scholars.lib.ntu.edu.tw/handle/123456789/520089
標題: | LRRK2 G2019S mutation induces dendrite degeneration through mislocalization and phosphorylation of tau by recruiting autoactivated GSK3β | 作者: | CHIN-HSIEN LIN Tsai P.-I. RUEY-MEEI WU Chien C.-T. |
公開日期: | 2010 | 出版社: | Society for Neuroscience | 卷: | 30 | 期: | 39 | 起(迄)頁: | 13138-13149 | 來源出版物: | Journal of Neuroscience | 摘要: | Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila dendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by the Drosophila glycogen synthase kinase 3β homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration. Copyright ? 2010 the authors. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-77957377567&doi=10.1523%2fJNEUROSCI.1737-10.2010&partnerID=40&md5=17dfc56480ab2956aa6818a9cd1ec968 https://scholars.lib.ntu.edu.tw/handle/123456789/520089 |
ISSN: | 0270-6474 | DOI: | 10.1523/JNEUROSCI.1737-10.2010 | SDG/關鍵字: | glycogen synthase kinase 3beta; leucine rich repeat kinase 2; tau protein; Drosophila protein; glycogen synthase kinase 3; LRRK2 protein, human; protein serine threonine kinase; shaggy protein, Drosophila; tau protein; animal experiment; animal model; article; controlled study; dendrite; Drosophila; enzyme localization; enzyme phosphorylation; gene mutation; genetic analysis; nerve cell degeneration; nerve cell lesion; nonhuman; priority journal; protein expression; protein function; amino acid substitution; animal; dendrite; Drosophila melanogaster; enzyme activation; enzymology; genetics; human; metabolism; mutation; nerve degeneration; pathology; phosphorylation; physiology; transgenic animal; Amino Acid Substitution; Animals; Animals, Genetically Modified; Dendrites; Drosophila melanogaster; Drosophila Proteins; Enzyme Activation; Glycogen Synthase Kinase 3; Humans; Mutation; Nerve Degeneration; Phosphorylation; Protein-Serine-Threonine Kinases; tau Proteins |
顯示於: | 醫學系 |
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