Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis

被引：99

作者：

Zhao, Yingjun ^{[1
,2
]}

Tseng, I-Chu ^{[2
]}

Heyser, Charles J. ^{[3
]}

Rockenstein, Edward ^{[3
]}

Mante, Michael ^{[3
]}

Adame, Anthony ^{[3
]}

Zheng, Qiuyang ^{[1
,2
]}

Huang, Timothy ^{[2
]}

Wang, Xin ^{[1
]}

Arslan, Pharhad E. ^{[4
]}

Chakrabarty, Paramita ^{[5
]}

Wu, Chengbiao ^{[3
]}

Bu, Guojun ^{[1
]}

Mobley, William C. ^{[3
]}

Zhang, Yun-wu ^{[1
,2
]}

St George-Hyslop, Peter ^{[6
,7
]}

Masliah, Eliezer ^{[3
,8
]}

Fraser, Paul ^{[4
,6
]}

Xu, Huaxi ^{[1
,2
]}

机构：

[1] Xiamen Univ, Inst Neurosci, Coll Med, Fujian Prov Key Lab Neurodegenerat Dis & Aging Re, Xiamen 361102, Fujian, Peoples R China

[2] Sanford Burnham Prebys Med Discovery Inst, Degenerat Dis Program, La Jolla, CA 92037 USA

[3] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[4] Tanz Ctr Res Neurodegenerat Dis, Toronto, ON M5T 2S8, Canada

[5] Univ Florida, Ctr Translat Res Neurodegenerat Dis, Dept Neurosci, Gainesville, FL 32610 USA

[6] Univ Toronto, Dept Med Biophys & Med Neurol, Toronto, ON M5S 3H2, Canada

[7] Univ Cambridge, Cambridge Inst Med Res, Dept Clin Neurosci, Cambridge CB2 0XY, England

[8] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

来源：

NEURON | 2015年 / 87卷 / 05期

基金：

中国国家自然科学基金;

关键词：

ALZHEIMERS-DISEASE; SYNAPTIC DYSFUNCTION; MOUSE MODEL; NEUROFIBRILLARY TANGLES; FILAMENTOUS TAU; TRANSGENIC MICE; PROTEIN-TAU; MUTATION; GENE; NEURODEGENERATION;

D O I：

10.1016/j.neuron.2015.08.020

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Progressive supranuclear palsy (PSP) is a movement disorder characterized by tau neuropathology where the underlying mechanism is unknown. An SNP (rs1768208 C/T) has been identified as a strong risk factor for PSP. Here, we identified a much higher T-allele occurrence and increased levels of the proapoptotic protein appoptosin in PSP patients. Elevations in appoptosin correlate with activated caspase-3 and caspase-cleaved tau levels. Appoptosin overexpression increased caspase-mediated tau cleavage, tau aggregation, and synaptic dysfunction, whereas appoptosin deficiency reduced tau cleavage and aggregation. Appoptosin transduction impaired multiple motor functions and exacerbated neuropathology in tau-transgenic mice in a manner dependent on caspase-3 and tau. Increased appoptosin and caspase-3-cleaved tau were also observed in brain samples of patients with Alzheimer's disease and frontotemporal dementia with tau inclusions. Our findings reveal a novel role for appoptosin in neurological disorders with tau neuropathology, linking caspase-3-mediated tau cleavage to synaptic dysfunction and behavioral/motor defects.

引用

页码：963 / 975

页数：13

共 50 条

[1]

Association of an extended haplotype in the tau gene with progressive supranuclear palsy [J].