Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling

Nat Med. 2016 Jan;22(1):46-53. doi: 10.1038/nm.4011. Epub 2015 Dec 21.

Abstract

The ubiquitin proteasome system (UPS) degrades misfolded proteins including those implicated in neurodegenerative diseases. We investigated the effects of tau accumulation on proteasome function in a mouse model of tauopathy and in a cross to a UPS reporter mouse (line Ub-G76V-GFP). Accumulation of insoluble tau was associated with a decrease in the peptidase activity of brain 26S proteasomes, higher levels of ubiquitinated proteins and undegraded Ub-G76V-GFP. 26S proteasomes from mice with tauopathy were physically associated with tau and were less active in hydrolyzing ubiquitinated proteins, small peptides and ATP. 26S proteasomes from normal mice incubated with recombinant oligomers or fibrils also showed lower hydrolyzing capacity in the same assays, implicating tau as a proteotoxin. Administration of an agent that activates cAMP-protein kinase A (PKA) signaling led to attenuation of proteasome dysfunction, probably through proteasome subunit phosphorylation. In vivo, this led to lower levels of aggregated tau and improvements in cognitive performance.

Publication types

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

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cognition / drug effects
  • Cognition Disorders / metabolism*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Disease Models, Animal
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • In Vitro Techniques
  • Mice
  • Mice, Transgenic
  • Native Polyacrylamide Gel Electrophoresis
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Aggregation, Pathological / metabolism
  • Rolipram / pharmacology
  • Signal Transduction / drug effects
  • Tauopathies / metabolism*
  • Ubiquitination
  • tau Proteins / metabolism*

Substances

  • Phosphodiesterase 4 Inhibitors
  • tau Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • Rolipram