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Conference Paper: Molecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Disease

TitleMolecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Disease
Authors
Issue Date2012
Citation
The 2012 Hong Kong-Taiwan Physiology Symposium and Joint Scientific Meeting of Hong Kong Society of Neurosciences (HKSN) & The Biophysical Society of Hong Kong (BPHK), The Chinese University of Hong Kong, Hong Kong, China, 14-15 June 2012, p. 51, abstract no. P13 How to Cite?
AbstractPresenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS associated with familial Alzheimer’s disease (FAD) increase the Aβ plaques formation in the brain and cause neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt intracellular calcium (Ca2+) regulation. Accumulating evidence suggests that Ca2+ disruption may play a proximal role in the AD pathogenesis. Mutant PS exaggerated Ca2+ release from the endoplasmic reticulum (ER). It also attenuated Ca2+ entry through the capacitative Ca2+ entry (CCE) pathway, yet, the mechanism is not fully understood. Using a human neuroblast cell line SH-SY5Y and Ca2+ imaging technique, we observed CCE deficits in FAD-linked PS1-M146L retroviral infected cell. The attenuation of CCE in PS1 mutant cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, we identified a molecular interaction between PS and STIM1 proteins by immunoprecipitation. On the other hand, immunofluorescence staining showed a significant reduction in puncta formation after ER Ca2+ depleted by thapsigargin in cells infected with PS1-M146L as compared to the wild type PS1 infected cells. Taken together, our results suggest a molecular mechanism for the CCE deficits in FAD associated with PS1 mutations. The interaction of mutant PS1 with STIM1 exerts a negative impact on its oligomerization and/or its interaction with Orai1. Our results may suggest molecular targets for the development of therapeutic agents that help to treat the disease.
DescriptionPoster Presentation
Persistent Identifierhttp://hdl.handle.net/10722/153112

 

DC FieldValueLanguage
dc.contributor.authorTong, CKBen_US
dc.contributor.authorFoskett, JKen_US
dc.contributor.authorCheung, KHen_US
dc.date.accessioned2012-07-16T09:57:07Z-
dc.date.available2012-07-16T09:57:07Z-
dc.date.issued2012en_US
dc.identifier.citationThe 2012 Hong Kong-Taiwan Physiology Symposium and Joint Scientific Meeting of Hong Kong Society of Neurosciences (HKSN) & The Biophysical Society of Hong Kong (BPHK), The Chinese University of Hong Kong, Hong Kong, China, 14-15 June 2012, p. 51, abstract no. P13en_US
dc.identifier.urihttp://hdl.handle.net/10722/153112-
dc.descriptionPoster Presentation-
dc.description.abstractPresenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS associated with familial Alzheimer’s disease (FAD) increase the Aβ plaques formation in the brain and cause neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt intracellular calcium (Ca2+) regulation. Accumulating evidence suggests that Ca2+ disruption may play a proximal role in the AD pathogenesis. Mutant PS exaggerated Ca2+ release from the endoplasmic reticulum (ER). It also attenuated Ca2+ entry through the capacitative Ca2+ entry (CCE) pathway, yet, the mechanism is not fully understood. Using a human neuroblast cell line SH-SY5Y and Ca2+ imaging technique, we observed CCE deficits in FAD-linked PS1-M146L retroviral infected cell. The attenuation of CCE in PS1 mutant cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, we identified a molecular interaction between PS and STIM1 proteins by immunoprecipitation. On the other hand, immunofluorescence staining showed a significant reduction in puncta formation after ER Ca2+ depleted by thapsigargin in cells infected with PS1-M146L as compared to the wild type PS1 infected cells. Taken together, our results suggest a molecular mechanism for the CCE deficits in FAD associated with PS1 mutations. The interaction of mutant PS1 with STIM1 exerts a negative impact on its oligomerization and/or its interaction with Orai1. Our results may suggest molecular targets for the development of therapeutic agents that help to treat the disease.-
dc.languageengen_US
dc.relation.ispartofHong Kong-Taiwan Physiology Symposium and HKSN / BOHK Joint Scientific Meetingen_US
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleMolecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Diseaseen_US
dc.typeConference_Paperen_US
dc.identifier.emailCheung, KH: ckingho@hku.hken_US
dc.identifier.authorityCheung, KH=rp01463en_US
dc.description.naturepublished_or_final_version-
dc.identifier.hkuros200824en_US
dc.identifier.spage51, abstract no. P13-
dc.identifier.epage51, abstract no. P13-

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