老年痴呆实验动物模型研制进展PPT课件.ppt

a-synuclein tau vesicles Tau aggregation/hyperphosphorylation Decreased MT bound tau MT depolymerization Impaired axonal transport Axonal degeneration disconnection Microtubules Pathological aggregates Deleterious Effects Of Tau Amyloidosis * 人类六个 tau 蛋白亚型的形成 Human tau gene is alternatively spliced to produce six isoforms Exons: 0 1 2 3 4 4a 5 6 7 8 9 10 11 12 13 14 E2 E3 R1 R1 R1 R1 R1 R1 R2 R2 R2 R3 R3 R3 R3 R3 R3 R4 R4 R4 R4 R4 R4 1 1 1 1 1 1 441 412 383 410 381 352 Tau ProteinIsoforms 4R/2N 4R/1N 4R/0N 3R/2N 3R/1N 3R/0N E2 E2 E2 E3 Amino terminal repeats 氨基末端重复序列 Microtubule binding repeats Alternatively spliced GENE Transcribed Alternatively spliced Translated 微管结合重复序列 * Tau基因的变异Mutations in the Tau Gene EXON 1 EXON 9 EXON 11 EXON 12 EXON 13 K257T I260V G272V E342V V337M R406W G389R R5H/L L266V S320F K369I --AAUAAGAAGCUGGAUCUU--AAT--CCG Intron 9 N279K L284L DN296N296H N296N DK280 L315R S352L Q336R EXON 10 P301S P301L S305N S305S INTRON 10 SPLICE SILENCER INTRON 10 SPLICE MODULATOR Intron 10 +3 +11 +13 +12 +14 +16 EXON 10 The R406W mutation, located on exon 13 of the tau gene, was identified in 3 distinct FTDP-17 kindreds. 精氨酸 色氨酸 * 正常 Tau蛋白的功能Normal Tau Protein 大量的低分子重量的微管相关旦白 An abundant low molecular weight microtubule-associated protein 分布在轴突 predominantly in axons 促进并稳定微管聚合, 维持正常的神经元轴突转运 Promotes microtubule (MT) polymerization, binds to MTs and stabilizes MTs 磷酸化降低与微管的结合能力 Phosphorylation negatively regulates the binding of tau to MTs * 正常Tau旦白的功能: 稳定微管并维持正常的神经元轴突转运Normal Tau Stabilizes MTs To Maintain Neuronal Transport  Tau病变引起神经元轴突转运障碍 While Tau Pathology Can Disrupt Neuronal Transport With Catastrophic Consequences Equivalent To A Train Wreck 假说 Hypothesis * R406W Tau 转基因小鼠的研制 Generation of T40hWT and T40R406W Tau Tg mice 精氨酸 色氨酸 Bin Zhang, Makoto Higuchi, Yasumasa Yoshiyama, Takeshi Ishihara, Mark S. Forman, Dan Martinez, Sonali Joyce, John