Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS

PLoS One. 2015 Aug 19;10(8):e0135570. doi: 10.1371/journal.pone.0135570. eCollection 2015.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by loss of motor neurons. The mechanisms leading to motor neuron degeneration in ALS are unclear. However, there is evidence for involvement of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in ALS, notably in mutant SOD1 mediated models of ALS. Stress induced phosphorylation of the eIF2 alpha subunit by eukaryotic translation initiation factor 2-alpha kinase 3 Perk activates the UPR. Guanabenz is a centrally acting alpha2 adrenergic receptor agonist shown to interact with a regulatory subunit of the protein phosphatase, Pp1/Gadd34, and selectively disrupt the dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eif2alpha). Here we demonstrate that guanabenz is protective in fibroblasts expressing G93A mutant SOD1 when they are exposed to tunicamycin mediated ER stress. However, in contrast to other reports, guanabenz treatment accelerated ALS-like disease progression in a strain of mutant SOD1 transgenic ALS mice. This study highlights challenges of pharmacological interventions of cellular stress responses in whole animal models of ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / pharmacology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Antihypertensive Agents / pharmacology
  • Disease Models, Animal
  • Disease Progression
  • Endoplasmic Reticulum Stress / drug effects*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fibroblasts / drug effects
  • Guanabenz / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Degeneration / pathology
  • Phosphorylation
  • Protein Phosphatase 1 / metabolism
  • Superoxide Dismutase / drug effects*
  • Superoxide Dismutase / genetics
  • Tunicamycin
  • Unfolded Protein Response
  • eIF-2 Kinase / metabolism

Substances

  • Adrenergic alpha-2 Receptor Agonists
  • Antihypertensive Agents
  • Eukaryotic Initiation Factor-2
  • Tunicamycin
  • SOD1 G93A protein
  • Superoxide Dismutase
  • PERK kinase
  • eIF-2 Kinase
  • Ppp1r15a protein, mouse
  • Protein Phosphatase 1
  • Guanabenz

Grant support

The authors received no specific funding for this work. The ALS Therapy Development Institute is a not-for-profit independent 503c organization funded primarily by private donations. The private donations come from 10's of thousands of ALS patients and their families and friends. These revenues are disclosed yearly in the authors' organization's audited financials (http://www.als.net/About-ALS-TDI/ALS-TDI-Annual-Reports.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.