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

Yingjun Zhao, I. Chu Tseng, Charles J. Heyser, Edward Rockenstein, Michael Mante, Anthony Adame, Qiuyang Zheng, Timothy Huang, Xin Wang, Pharhad E. Arslan, Paramita Chakrabarty, Chengbiao Wu, Guojun D Bu, William C. Mobley, Yun wu Zhang, Peter St. George-Hyslop, Eliezer Masliah, Paul Fraser, Huaxi Xu

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

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 pro-apoptotic 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.

Original languageEnglish (US)
Pages (from-to)963-975
Number of pages13
JournalNeuron
Volume87
Issue number5
DOIs
StatePublished - Sep 2 2015
Externally publishedYes

Fingerprint

Progressive Supranuclear Palsy
Caspases
Caspase 3
Alzheimer Disease
Frontotemporal Dementia
Apoptosis Regulatory Proteins
Movement Disorders
Nervous System Diseases
Transgenic Mice
Single Nucleotide Polymorphism
Alleles
Brain
Neuropathology

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhao, Y., Tseng, I. C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., ... Xu, H. (2015). Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. Neuron, 87(5), 963-975. https://doi.org/10.1016/j.neuron.2015.08.020

Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. / Zhao, Yingjun; Tseng, I. Chu; Heyser, Charles J.; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Zheng, Qiuyang; Huang, Timothy; Wang, Xin; Arslan, Pharhad E.; Chakrabarty, Paramita; Wu, Chengbiao; Bu, Guojun D; Mobley, William C.; Zhang, Yun wu; St. George-Hyslop, Peter; Masliah, Eliezer; Fraser, Paul; Xu, Huaxi.

In: Neuron, Vol. 87, No. 5, 02.09.2015, p. 963-975.

Research output: Contribution to journalArticle

Zhao, Y, Tseng, IC, Heyser, CJ, Rockenstein, E, Mante, M, Adame, A, Zheng, Q, Huang, T, Wang, X, Arslan, PE, Chakrabarty, P, Wu, C, Bu, GD, Mobley, WC, Zhang, YW, St. George-Hyslop, P, Masliah, E, Fraser, P & Xu, H 2015, 'Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis', Neuron, vol. 87, no. 5, pp. 963-975. https://doi.org/10.1016/j.neuron.2015.08.020
Zhao, Yingjun ; Tseng, I. Chu ; Heyser, Charles J. ; Rockenstein, Edward ; Mante, Michael ; Adame, Anthony ; Zheng, Qiuyang ; Huang, Timothy ; Wang, Xin ; Arslan, Pharhad E. ; Chakrabarty, Paramita ; Wu, Chengbiao ; Bu, Guojun D ; Mobley, William C. ; Zhang, Yun wu ; St. George-Hyslop, Peter ; Masliah, Eliezer ; Fraser, Paul ; Xu, Huaxi. / Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis. In: Neuron. 2015 ; Vol. 87, No. 5. pp. 963-975.
@article{71fbf464024c4f3780bbc947e3dc3d68,
title = "Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis",
abstract = "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 pro-apoptotic 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.",
author = "Yingjun Zhao and Tseng, {I. Chu} and Heyser, {Charles J.} and Edward Rockenstein and Michael Mante and Anthony Adame and Qiuyang Zheng and Timothy Huang and Xin Wang and Arslan, {Pharhad E.} and Paramita Chakrabarty and Chengbiao Wu and Bu, {Guojun D} and Mobley, {William C.} and Zhang, {Yun wu} and {St. George-Hyslop}, Peter and Eliezer Masliah and Paul Fraser and Huaxi Xu",
year = "2015",
month = "9",
day = "2",
doi = "10.1016/j.neuron.2015.08.020",
language = "English (US)",
volume = "87",
pages = "963--975",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis

AU - Zhao, Yingjun

AU - Tseng, I. Chu

AU - Heyser, Charles J.

AU - Rockenstein, Edward

AU - Mante, Michael

AU - Adame, Anthony

AU - Zheng, Qiuyang

AU - Huang, Timothy

AU - Wang, Xin

AU - Arslan, Pharhad E.

AU - Chakrabarty, Paramita

AU - Wu, Chengbiao

AU - Bu, Guojun D

AU - Mobley, William C.

AU - Zhang, Yun wu

AU - St. George-Hyslop, Peter

AU - Masliah, Eliezer

AU - Fraser, Paul

AU - Xu, Huaxi

PY - 2015/9/2

Y1 - 2015/9/2

N2 - 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 pro-apoptotic 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.

AB - 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 pro-apoptotic 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.

UR - http://www.scopus.com/inward/record.url?scp=84940500649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84940500649&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2015.08.020

DO - 10.1016/j.neuron.2015.08.020

M3 - Article

C2 - 26335643

AN - SCOPUS:84940500649

VL - 87

SP - 963

EP - 975

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 5

ER -