FRMD4A-cytohesin signaling modulates the cellular release of tau

J Cell Sci. 2016 May 15;129(10):2003-15. doi: 10.1242/jcs.180745. Epub 2016 Apr 4.


One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein. Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase Cζ (aPKCζ) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.

Keywords: Alzheimer's disease; Functional genomics; Neurodegenerative disease; PARD6A; Polarity signaling; Risk gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • Adaptor Proteins, Signal Transducing / genetics*
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Gene Expression Regulation
  • Guanine Nucleotide Exchange Factors / genetics*
  • HEK293 Cells
  • Humans
  • Neurogenesis / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • Phosphorylation
  • Protein Aggregation, Pathological / genetics
  • Signal Transduction
  • tau Proteins / genetics*
  • tau Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • FERM domain-containing protein 4A, human
  • Guanine Nucleotide Exchange Factors
  • PARD6A protein, human
  • cytohesin-1
  • tau Proteins
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6