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

47 Scopus citations

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

ASJC Scopus subject areas

  • Neuroscience(all)

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    Zhao, Y., Tseng, I. C., Heyser, C. J., Rockenstein, E., Mante, M., Adame, A., Zheng, Q., Huang, T., Wang, X., Arslan, P. E., Chakrabarty, P., Wu, C., Bu, G. D., Mobley, W. C., Zhang, Y. W., St. George-Hyslop, P., Masliah, E., Fraser, P., & 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