Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B.
Deprenyl and other propargylamines are clinically beneficial in Parkinson's disease (PD). The benefits were thought to depend on monoamine oxidase B (MAO-B) inhibition. A large body of research has now shown that the propargylamines increase neuronal survival independently of MAO-B inhibition by interfering with apoptosis signaling pathways. The propargylamines bind to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The GAPDH binding is associated with decreased synthesis of pro-apoptotic proteins like BAX, c-JUN and GAPDH but increased synthesis of anti-apoptotic proteins like BCL-2, Cu-Zn superoxide dismutase and heat shock protein 70. Anti-apoptotic propargylamines that do not inhibit MAO-B are now in PD clinical trial.
Tatton
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Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA. william.tatton@mssm.edu
Chalmers-Redman
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Tatton
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010293:Pargyline / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D011437:Propylamines / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology* / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D011437:Propylamines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D051028:bcl-2-Associated X Protein; C009054:propargylamine; D012642:Selegiline; D010293:Pargyline; D013482:Superoxide Dismutase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D008995:Monoamine Oxidase