Appoptosin-Mediated Caspase Cleavage of Tau Contributes to Progressive Supranuclear Palsy Pathogenesis.
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.
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.
Yingjun
Y
Zhao
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
I-Chu
IC
Tseng
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
Charles J
CJ
Heyser
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
Edward
E
Rockenstein
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
Michael
M
Mante
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
Anthony
A
Adame
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.
Qiuyang
Q
Zheng
Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Timothy
T
Huang
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Xin
X
Wang
Tanz Centre for Research in Neurodegenerative Diseases, Krembil Discovery Tower, Toronto, ON M5T 2S8, Canada.
Pharhad E
PE
Arslan
Department of Neuroscience, Center for Translational Research in Neurodegenerative Diseases, University of Florida, Gainesville, FL 32610, USA.
Paramita
P
Chakrabarty
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
Chengbiao
C
Wu
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
Guojun
G
Bu
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
William C
WC
Mobley
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.
Yun-Wu
YW
Zhang
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.
Peter
P
St George-Hyslop
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.
Eliezer
E
Masliah
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.
Paul
P
Fraser
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.
Huaxi
H
Xu
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D018737:Hand Strength / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051381:Rats; D013494:Supranuclear Palsy, Progressive / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C560487:MOBP protein, human; D009185:Myelin Proteins; D016875:tau Proteins; D053148:Caspase 3