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Conference Paper: Gamma-secretase cleaves stromal interaction molecule 1 induces capacitative calcium entry deficits in familial Alzheimer's disease

TitleGamma-secretase cleaves stromal interaction molecule 1 induces capacitative calcium entry deficits in familial Alzheimer's disease
Authors
Issue Date2016
PublisherThe University of Hong Kong.
Citation
The 2016 Neuroscience Symposium and Annual Scientific Conference of the Hong Kong Society of Neurosciences, The University of Hong Kong, Hong Kong, 18 May 2016. In Programme Book, 2016, p. 52, abstract no. P43 How to Cite?
AbstractAlzheimer’s disease (AD) is the most common form of dementia and mounting evidence suggests calcium (Ca2+) disruption is its proximal pathogenic origin. Ca2+ dysregulation observed in cells expressing familial Alzheimer’s disease (FAD)- causing presenilins (PS) has been attributed to the exaggerated Ca2+ release and the attenuated store-operated Ca2+ entry (also known as capacitative Ca2+ entry, CCE). Several mechanisms have been proposed for the exaggerated Ca2+ release, yet the underlying molecular mechanisms for attenuated CCE remain elusive. In this study we employed Ca2+ imaging, FRET microscopy, in situ proximity ligation assay, in vitro γ-secretase cleavage assay and primary neuronal culture to delineate the mechanism for CCE attenuation and its linkage to AD pathology. We showed that the attenuation of CCE depends upon PS-associated γ-secretase activity. PS1 and STIM1 interact in human neuroblastoma SH-SY5Y cells, and mutant PS1 enhances γ-secretase cleavage of STIM1 in the transmembrane domain that has high similarity with amyloid precursor protein. Furthermore, FAD PS1-induced CCE attenuation destabilizes mature dendritic spines that are rescued by γ-secretase inhibition or overexpression of STIM1. Our results suggest a molecular mechanism of CCE deficits in which FAD-mutant PS1 enhances γ-secretase cleavage of STIM1, reducing recruitment of Orai1 that results in impaired CCE. These findings indicate a physiological role of PS1/γ-secretase in modulating the availability of STIM1 for CCE, and suggest that identification of STIM1 as a substrate of γ-secretase provides a novel therapeutic target for the treatment of AD.
DescriptionConference Theme: Nature and Nurture in Brain Functions
Persistent Identifierhttp://hdl.handle.net/10722/231520

 

DC FieldValueLanguage
dc.contributor.authorTong, CKB-
dc.contributor.authorLai, KO-
dc.contributor.authorCheung, KH-
dc.date.accessioned2016-09-20T05:23:42Z-
dc.date.available2016-09-20T05:23:42Z-
dc.date.issued2016-
dc.identifier.citationThe 2016 Neuroscience Symposium and Annual Scientific Conference of the Hong Kong Society of Neurosciences, The University of Hong Kong, Hong Kong, 18 May 2016. In Programme Book, 2016, p. 52, abstract no. P43-
dc.identifier.urihttp://hdl.handle.net/10722/231520-
dc.descriptionConference Theme: Nature and Nurture in Brain Functions-
dc.description.abstractAlzheimer’s disease (AD) is the most common form of dementia and mounting evidence suggests calcium (Ca2+) disruption is its proximal pathogenic origin. Ca2+ dysregulation observed in cells expressing familial Alzheimer’s disease (FAD)- causing presenilins (PS) has been attributed to the exaggerated Ca2+ release and the attenuated store-operated Ca2+ entry (also known as capacitative Ca2+ entry, CCE). Several mechanisms have been proposed for the exaggerated Ca2+ release, yet the underlying molecular mechanisms for attenuated CCE remain elusive. In this study we employed Ca2+ imaging, FRET microscopy, in situ proximity ligation assay, in vitro γ-secretase cleavage assay and primary neuronal culture to delineate the mechanism for CCE attenuation and its linkage to AD pathology. We showed that the attenuation of CCE depends upon PS-associated γ-secretase activity. PS1 and STIM1 interact in human neuroblastoma SH-SY5Y cells, and mutant PS1 enhances γ-secretase cleavage of STIM1 in the transmembrane domain that has high similarity with amyloid precursor protein. Furthermore, FAD PS1-induced CCE attenuation destabilizes mature dendritic spines that are rescued by γ-secretase inhibition or overexpression of STIM1. Our results suggest a molecular mechanism of CCE deficits in which FAD-mutant PS1 enhances γ-secretase cleavage of STIM1, reducing recruitment of Orai1 that results in impaired CCE. These findings indicate a physiological role of PS1/γ-secretase in modulating the availability of STIM1 for CCE, and suggest that identification of STIM1 as a substrate of γ-secretase provides a novel therapeutic target for the treatment of AD.-
dc.languageeng-
dc.publisherThe University of Hong Kong. -
dc.relation.ispartofNeuroscience Symposium & Annual Scientific Conference of the Hong Kong Society of Neurosciences, HKSN 2016-
dc.titleGamma-secretase cleaves stromal interaction molecule 1 induces capacitative calcium entry deficits in familial Alzheimer's disease-
dc.typeConference_Paper-
dc.identifier.emailLai, KO: laiko@hku.hk-
dc.identifier.emailCheung, KH: kingho.cheung@hku.hk-
dc.identifier.authorityLai, KO=rp01891-
dc.identifier.authorityCheung, KH=rp01463-
dc.identifier.hkuros266384-
dc.identifier.spage52, abstract no. P43-
dc.identifier.epage52, abstract no. P43-
dc.publisher.placeHong Kong-

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