A novel decoy that interrupts G93A-superoxide dismutase gain of interaction with malate dehydrogenase improves survival in an amyotrophic lateral sclerosis cell model.
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 new route in ALS drug research.
Mali
Yael
Y
Department of Neurobiology, Tel Aviv University, Tel Aviv 69978, Israel.
Zisapel
Nava
N
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D008291:Malate Dehydrogenase / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D012402:Rotenone / Q000633:toxicity; D013482:Superoxide Dismutase / Q000378:metabolism*
D010455:Peptides; D012402:Rotenone; D000255:Adenosine Triphosphate; D008291:Malate Dehydrogenase; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D005947:Glucose