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Article: PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion

TitlePMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion
Authors
KeywordsPMCA
ATP2B4
Calcium transient
Familial spastic paraplegia
Neurodegeneration
Issue Date2015
PublisherJohn Wiley & Sons Ltd.. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2157-9032
Citation
Brain and Behavior , 2015, v. 5 n. 4, p. 1-6 How to Cite?
AbstractBackground: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. Methods: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Results: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Conclusion: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/211823
ISSN
2023 Impact Factor: 2.6
2023 SCImago Journal Rankings: 0.908
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorHo, WL-
dc.contributor.authorPang, SYY-
dc.contributor.authorLi, M-
dc.contributor.authorTse, HM-
dc.contributor.authorKung, MHW-
dc.contributor.authorSham, PC-
dc.contributor.authorHo, SL-
dc.date.accessioned2015-07-21T02:12:03Z-
dc.date.available2015-07-21T02:12:03Z-
dc.date.issued2015-
dc.identifier.citationBrain and Behavior , 2015, v. 5 n. 4, p. 1-6-
dc.identifier.issn2162-3279-
dc.identifier.urihttp://hdl.handle.net/10722/211823-
dc.description.abstractBackground: Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation. Methods: As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4. Results: Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin. Conclusion: Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP. © 2015 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.-
dc.languageeng-
dc.publisherJohn Wiley & Sons Ltd.. The Journal's web site is located at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2157-9032-
dc.relation.ispartofBrain and Behavior-
dc.rightsBrain and Behavior . Copyright © John Wiley & Sons Ltd..-
dc.rightsSpecial Statement for Preprint only Before publication: 'This is a preprint of an article accepted for publication in [The Journal of Pathology] Copyright © ([year]) ([Pathological Society of Great Britain and Ireland])'. After publication: the preprint notice should be amended to follows: 'This is a preprint of an article published in [include the complete citation information for the final version of the Contribution as published in the print edition of the Journal]' For Cochrane Library/ Cochrane Database of Systematic Reviews, add statement & acknowledgement : ‘This review is published as a Cochrane Review in the Cochrane Database of Systematic Reviews 20XX, Issue X. Cochrane Reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and the Cochrane Database of Systematic Reviews should be consulted for the most recent version of the Review.’ Please include reference to the Review and hyperlink to the original version using the following format e.g. Authors. Title of Review. Cochrane Database of Systematic Reviews 20XX, Issue #. Art. No.: CD00XXXX. DOI: 10.1002/14651858.CD00XXXX (insert persistent link to the article by using the URL: http://dx.doi.org/10.1002/14651858.CD00XXXX) (This statement should refer to the most recent issue of the Cochrane Database of Systematic Reviews in which the Review published.)-
dc.subjectPMCA-
dc.subjectATP2B4-
dc.subjectCalcium transient-
dc.subjectFamilial spastic paraplegia-
dc.subjectNeurodegeneration-
dc.titlePMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion-
dc.typeArticle-
dc.identifier.emailHo, WL: hwl2002@hku.hk-
dc.identifier.emailPang, SYY: syypang@hku.hk-
dc.identifier.emailLi, M: mxli@hku.hk-
dc.identifier.emailTse, HM: zerotse@HKUCC-COM.hku.hk-
dc.identifier.emailKung, MHW: mhwkung@hkucc.hku.hk-
dc.identifier.emailSham, PC: pcsham@hku.hk-
dc.identifier.emailHo, SL: slho@hku.hk-
dc.identifier.authorityHo, WL=rp00259-
dc.identifier.authorityLi, M=rp01722-
dc.identifier.authoritySham, PC=rp00459-
dc.identifier.authorityHo, SL=rp00240-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1002/brb3.321-
dc.identifier.pmid25798335-
dc.identifier.scopuseid_2-s2.0-84926524596-
dc.identifier.hkuros245343-
dc.identifier.volume5-
dc.identifier.issue4-
dc.identifier.spage1-
dc.identifier.epage6-
dc.identifier.isiWOS:000352799300005-
dc.publisher.placeUnited Kingdom-
dc.identifier.issnl2162-3279-

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