A new study led by scientists from the ALS Therapy Development Institute (ALS TDI) underscores the complexity of therapeutic interventions that perturb ER stress and the unfolded protein response (UPR), pathways which are involved in ALS. Guanabenz is an alpha2 adrenergic receptor agonist approved for use in humans, which also inhibits dephosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) and prolongs activation of the UPR (see April 2015 news). Although earlier studies have shown that guanbenz treatment ameliorates survival in the mSOD1 mouse model of ALS, a new study published Aug 19 in PLOS ONE presents efficacy data with two different guanabenz treatment protocols suggesting that the drug accelerates onset of paralysis and shortens lifespan in this preclinical model, despite beneficial effects in cellular models of ER stress. Although differences in study design my underlie some of the discrepancies, these finding also suggest that the timing and target-selectivity are particularly important when perturbing the intricate network of pathways involved in the UPR.
Click here to read the press release.
Vieira FG, Ping Q, Moreno AJ, Kidd JD, Thompson K, Jiang B, Lincecum JM, Wang MZ, De Zutter GS, Tassinari VR, Levine B, Hatzipetros T, Gill A, Perrin S. Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS. PLOS ONE. 2015 August 19. DOI: 10.1371/journal.pone.0135570. [Full Text].