title: Calpain-mediated cleavage of DARPP-32 in Alzheimer's disease.
abstract: Toxicity induced by aberrant protein aggregates in Alzheimer's disease (AD) causes synaptic disconnection and concomitant progressive neurodegeneration that eventually impair cognitive function. cAMP-response element-binding protein (CREB) is a transcription factor involved in the molecular switch that converts short-term to long-term memory. Although disturbances in CREB function have been suggested to cause memory deficits in both AD and AD animal models, the mechanism of CREB dysfunction is still unclear. Here, we show that the dopamine- and cAMP-regulated phosphoprotein 32 kDa (DARPP-32), a key inhibitor of protein phosphate-1 (PP-1) that regulates CREB phosphorylation, is cleaved by activated calpain in both AD brains and neuronal cells treated with amyloid-β or okadaic acid, a protein phosphatase-2A inhibitor that induces tau hyperphosphorylation and neuronal death. We found that DARPP-32 is mainly cleaved at Thr(153) by calpain and that this cleavage of DARPP-32 reduces CREB phosphorylation via loss of its inhibitory function on PP1. Our results suggest a novel mechanism of DARPP-32-CREB signalling dysregulation in AD.
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Cho
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Mi-Hyang
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jung-Han
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jongjin
authors.initials: J
authors.lastname: Peak
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Kyoung-Hye
authors.initials: KH
authors.lastname: Kong
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Alzheimer's Disease Experts Lab (ADEL), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.|Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea.|Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea.|Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Dong-Hou
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human; D011994:Recombinant Proteins; D002154:Calpain
keywords: Alzheimer's disease; DARPP-32; cAMP-response element-binding protein; calpain; okadaic acid; protein kinase A