Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis

Erez Eitan, Ailon Tichon, Aviv Gazit, Daniel Gitler, Shimon Slavin, Esther Priel

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Telomerase is expressed in the neonatal brain, in distinct regions of adult brain, and was shown to protect developing neurons from apoptosis. Telomerase reactivation by gene manipulation reverses neurodegeneration in aged telomerase-deficient mice. Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents. In this study, we demonstrate for the first time that the novel compound AGS-499 increases telomerase activity and expression in the mouse brain and spinal cord (SC). It exerts neuroprotective effects in NMDA-injected CD-1 mice, delays the onset and progression of the amyotrophic lateral sclerosis (ALS) disease in SOD1 transgenic mice, and, after the onset of ALS, it increases the survival of motor neurons in the SC by 60%. The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated. Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.

Original languageEnglish
Pages (from-to)313-329
Number of pages17
JournalEMBO Molecular Medicine
Volume4
Issue number4
DOIs
StatePublished - 1 Apr 2012

Keywords

  • ALS
  • Activator
  • Brain
  • Neuroprotector
  • Telomerase

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