Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies

J Exp Med. 2018 Dec 3;215(12):3038-3056. doi: 10.1084/jem.20180539. Epub 2018 Oct 29.

Abstract

SRPK2 is abnormally activated in tauopathies including Alzheimer's disease (AD). SRPK2 is known to play an important role in pre-mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre-mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and increases its nuclear translocation as well as kinase activity, augmenting exon 10 inclusion. Conversely, AEP-uncleavable SRPK2 N342A mutant increases exon 10 exclusion. Lentiviral expression of truncated SRPK2 increases 4R-tau isoforms and accelerates cognitive decline in htau mice. Uncleavable SRPK2 N342A expression improves synaptic functions and prevents spatial memory deficits in tau intronic mutant FTDP-17 transgenic mice. Hence, AEP mediates tau-splicing imbalance in tauopathies via cleaving SRPK2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amino Acid Substitution
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / metabolism*
  • Cognitive Dysfunction / pathology
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Mice
  • Mice, Knockout
  • Mutation, Missense
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Synapses / genetics
  • Synapses / metabolism
  • Synapses / pathology
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • tau Proteins
  • Srpk2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Amyloid Precursor Protein Secretases
  • Cysteine Endopeptidases
  • asparaginylendopeptidase