Guanabenz Treatment Accelerates Disease in a Mutant SOD1 Mouse Model of ALS.
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.
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Fernando G
FG
Vieira
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Qinggong
Q
Ping
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Andy J
AJ
Moreno
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Joshua D
JD
Kidd
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Kenneth
K
Thompson
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Bingbing
B
Jiang
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
John M
JM
Lincecum
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Monica Z
MZ
Wang
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Gerard S
GS
De Zutter
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Valerie R
VR
Tassinari
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Beth
B
Levine
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Theo
T
Hatzipetros
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Alan
A
Gill
ALS Therapy Development Institute, Cambridge, Massachusetts, United States of America.
Steven
S
Perrin
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects; D006143:Guanabenz / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000187:drug effects* / Q000235:genetics; D014415:Tunicamycin; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism
D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D015852:Eukaryotic Initiation Factor-2; D006143:Guanabenz; D054645:Protein Phosphatase 1; D013482:Superoxide Dismutase; D014415:Tunicamycin; D019892:eIF-2 Kinase; C109415:SOD1 G93A protein; C513256:Ppp1r15a protein, mouse