Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 17, Pages 5442-5448Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm900631m
Keywords
-
Categories
Funding
- ISF Morasha
- Gimmel-farb foundation
Ask authors/readers for more resources
Human G93A-superoxide dismutase-1 (G93AhSOD1) mutation causes amyotrophic lateral sclerosis (ALS) in rodents and humans, Recent observations indicate gain of interaction of G93AhSOD1 with cytosolic malate dehydrogenase (MDH1) and subsequent impairment in the malate aspartate shuttle which is vital to neurons. Using fluorescence resonance energy transfer (FRET), we screened an MDH1 derived peptide library for a decoy that would interrupt the G93AhSOD1-MDH1 interaction. A specific 23 amino acid blocker of this interaction was thus discovered, and interruption of interaction was confirmed by pull-down immunoprecipitation studies. A cell permeable 5-carboxytetramethylrhodamine derivative of the decoy peptide improved ATP content of motor neuron derived NSC-34 cells expressing G93AhSOD1 and enhanced cell survival under rotenone and low glucose challenges. Decoy agents capable of interrupting the gain of toxic interaction of G93AhSOD1 with MDH1 provide further evidence for the role of malate aspartate shuttle inhibition in G93AhSOD1 toxicity and a promising pew route in ALS drug research.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available