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Regulation of synapse weakening through interactions of the microtubule associated protein tau with pacsin1

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)7162-7170
Number of pages9
JournalJournal of Neuroscience
Issue number34
Published25 Aug 2021

Bibliographical note

Funding Information: P.R. and K.C. were supported by the Biotechnology and Biological Sciences Research Council. K.C., C.S., Y. L., S.J.M., S.-C.K., and S.A.B. were supported by the UK Dementia Research Institute, which receives its funding from DRI LTD, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. J.H.Y. was supported by the UK-Korea Alzheimer’s disease research consortium program under the Korea Ministry of Health and Welfare. K.C. was supported by the Wellcome Trust. The authors declare no competing financial interests. Correspondence should be addressed to Kwangwook Cho at Copyright © 2021 the authors Publisher Copyright: Copyright © 2021 the authors. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors


Hyperphosphorylation of the microtubule associated protein tau (tau) is inextricably linked to several neurodegenerative diseases, collectively termed tauopathies, in which synapse dysfunction occurs through largely unidentified mechanisms. Our research aimed to uncover molecular mechanisms by which phosphorylation of tau (pTau) affects synapse function. Using combined molecular and electrophysiological analysis with in vitro genetic knock-in of phosphorylation mutant human tau in male rat CA1 hippocampal neurons, we show an interplay between tau and protein kinase C and casein kinase substrate in neurons protein 1 (PACSIN1) that regulates synapse function. pTau at serine residues 396/404 decreases tau:PACSIN1 binding and evokes PACSIN1-dependent functional and structural synapse weakening. Knock-down of tau or PACSIN1 increases AMPA receptor (AMPAR)-mediated current at extrasynaptic regions, supporting a role for these proteins in affecting AMPAR trafficking. The pTau-induced PACSIN1 dissociation may represent a pathophysiological regulator of synapse function that underlies tauopathy-associated synapse defects.

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