Aspirin Molecule Targets Enzyme Active in Neurodegeneration

Researchers at the Boyce Thompson Institute and Johns Hopkins University have discovered that salicylic acid, the primary product from aspirin breakdown, binds to and blocks an enzyme thought to play a major role in neurodegenerative diseases, including Parkinson’s disease. The research paper, titled “Human GAPDH Is a Target of Aspirin’s Primary Metabolite Salicylic Acid and Its Derivatives,” was published in PLOS One.

Salicylic acid (SA) and its derivatives are prime examples of plant-derived molecules used in modern pharmaceuticals. Acetyl SA, commonly called aspirin, is the most popular drug in the world, with indications that include pain relief, fever, inflammation, and risk reduction of heart attack and strokes. SA is a compound of extreme importance in plants, being involved in physiological processes such as immunity. Due to its range of pharmacological effects, the scientific community theorizes that undiscovered targets for this chemical still exist.

Professor Daniel Klessig, at Boyce Thompson and Cornell University, has long focused his research on the activity of SA and its targets, primarily in plants, developing high-throughput screens to identify additional targets. To investigate SA targets in humans, the research team, under Professor Klessig’s leadership, employed similar screens of human cells and discovered several new potential protein targets for SA. One of them was Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), an enzyme that plays a central role in glycolysis, a metabolic process of energy production, DNA repair and transcription. Importantly, GAPDH has also been linked to cell death (apoptosis) induced by reactive oxygen species (ROS). Under oxidative stress, the enzyme enters the neuron nucleus and initiates molecular mechanisms that result in cell death. The team discovered that SA can bind to GAPDH, preventing its entry into the nucleus and the consequent cell death, an effect previously observed with the Parkinson’s drug therapy deprenyl. Researchers had previously observed that HMGB1 (High Mobility Group Box 1), involved in inflammation and associated with diseases such as lupus and arthritis, is another SA target.

Now, these novel data revealed that synthetic and natural derivatives of SA, such as one compound found in licorice, are more potent inhibitors than SA of both human GAPDH’s and HMGB1’s disease-associated bioactivities.

This evidence supports the theory that new and effective therapy compounds can be found in SA-derived molecules. Professor Klessig said of the study’s potential in a press release, “A better understanding of how salicylic acid and its derivatives regulate the activities of GAPDH and HMGB1, coupled with the discovery of much more potent synthetic and natural derivatives of salicylic acid, provide great promise for the development of new and better salicylic acid-based treatments of a wide variety of prevalent, devastating diseases.”