Our planned studies may provide new targets and treatment directions in amyotrophic lateral sclerosis (ALS), a fatal disease with no cure. Mutant (mt) SOD1 is thought to cause familial ALS (FALS) because of a gain in function probably involving misfolding of the protein. We recently published data that show that haploinsufficiency of PERK (which as part of the unfolded protein response [UPR] leads to phosphorylation of eIF2? with a subsequent suppression of translation) accelerates disease in G85R mtSOD1 FALS transgenic mice and have preliminary unpublished data that show that a knockdown of GADD34 (which dephosphorylates eIF2?) ameliorates disease. These data have led to the hypothesis underlying this proposal: an enhancement of PERK and the PERK pathway will ameliorate disease.
In Specific Aim I, we will test the efficacy of an FDA-approved drug, guanabenz, in ameliorating disease in G85R mtSOD1 FALS mice. Guanabenz was previously shown to promote clearance of scrapie prion protein (PrPsc) (a misfolded protein) in tissue-culture cells and also to significantly prolong survival of PrPsc transgenic mice. Guanabenz was very recently found to bind to a regulatory subunit of protein phosphatase 1, PPP1R15A/GADD34, selectively disrupting the stress-induced dephosphorylation of eIF2?. Guanabenz is an especially attractive drug for the treatment of FALS because a great deal is known about its pharmacokinetics (e.g., it is known to cross the blood-brain barrier) and safety due to its present use as an antihypertensive.
In Specific Aim II, we plan to activate PERK before the stress response is triggered, and also enhance PERK above the normal endogenous levels during ER stress (e.g., during disease). We will use adeno-associated virus9 (AAV9) to deliver Fv2E-PERK, which contains the kinase domain of PERK (that is normally activated by dimerization) fused to a protein module. Administration of a small dimerizer molecule (AP20187) leads to PERK activation, even in the absence of a stress response. The results of our studies will have implications for sporadic ALS as well as FALS because: recent data suggest that sporadic ALS may also involve abnormalities in the SOD1 protein or its activity;TDP-43, which is implicated in sporadic ALS and FALS, has potential interactions with the UPR since TDP-43 is misfolded in these diseases and because TDP-43 is a constituent of stress granules-which can form as a result of the UPR.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a desperate disease for which there is no cure and no effective treatment. It is accepted by many investigators that mutations in SOD1 cause familial ALS because they lead to misfolding of the protein. This proposal involves two different treatment approaches that allow the cell to enhance its normal response to misfolded proteins.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code