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Neuron. 2015 Sep 2;87(5):963-75. doi: 10.1016/j.neuron.2015.08.020.

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

Author information

1
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China; Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
2
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
3
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
4
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
5
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada.
6
Department of Neuroscience, Center for Translational Research in Neurodegenerative Diseases, University of Florida, Gainesville, FL 32610, USA.
7
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada; Department of Medical Biophysics and Medicine (Neurology), University of Toronto, Toronto, ON M5S 3H2, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
8
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
9
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada; Department of Medical Biophysics and Medicine (Neurology), University of Toronto, Toronto, ON M5S 3H2, Canada.
10
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China; Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: xuh@sbpdiscovery.org.

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.

PMID:
26335643
PMCID:
PMC4575284
DOI:
10.1016/j.neuron.2015.08.020
[Indexed for MEDLINE]
Free PMC Article

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