Pharmacological Inhibition of O-GlcNAcase Enhances Autophagy in Brain through an mTOR-Independent Pathway

ACS Chem Neurosci. 2018 Jun 20;9(6):1366-1379. doi: 10.1021/acschemneuro.8b00015. Epub 2018 Mar 5.

Abstract

The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. The mechanisms mediating the neuroprotective effects of OGA inhibitors, however, remain poorly understood. Here we show, using a range of methods in neuroblastoma N2a cells, in primary rat neurons, and in mouse brain, that selective OGA inhibitors stimulate autophagy through an mTOR-independent pathway without obvious toxicity. Additionally, OGA inhibition significantly decreased the levels of toxic protein species associated with AD pathogenesis in the JNPL3 tauopathy mouse model as well as the 3×Tg-AD mouse model. These results strongly suggest that OGA inhibitors act within brain through a mechanism involving enhancement of autophagy, which aids the brain in combatting the accumulation of toxic protein species. Our study supports OGA inhibition being a feasible therapeutic strategy for hindering the progression of AD and other neurodegenerative diseases. Moreover, these data suggest more targeted strategies to stimulate autophagy in an mTOR-independent manner may be found within the O-GlcNAc pathway. These findings should aid the advancement of OGA inhibitors within the clinic.

Keywords: Alzheimer’s disease; O-GlcNAc; Thiamet-G; autophagy; glycosylation; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Autophagy / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Disease Models, Animal
  • Humans
  • Neurons / drug effects
  • Protein Processing, Post-Translational / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / pharmacology*
  • Tauopathies / drug therapy
  • Tauopathies / metabolism
  • tau Proteins / drug effects
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat