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

Philip Regan, Scott J. Mitchell, Seung Chan Kim, Younbok Lee, Jee Hyun Yi, Saviana A. Barbati, Christopher Shaw, Kwangwook Cho*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)7162-7170
Number of pages9
JournalJournal of Neuroscience
Issue number34
Publication statusPublished - 25 Aug 2021


  • Alzheimer's disease
  • Ampa receptor
  • Pacsin1
  • Phosphorylation
  • Synapse
  • Tau


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