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Modulating ALS Related Amyloidogenic TDP-43(307-319) Oligomeric Aggregates with Computationally Derived Therapeutic Molecules.

TDP-43 aggregates are a salient feature for ALS, FTD and a variety of other neurodegenerative diseases including AD. With an anticipated growth in the most susceptible demographic, projections predict neurodegenerative diseases will potentially affect 15 million people in the United States by 2050. Currently there are no cures for ALS, FTD or AD. Previous studies on the amyloidogenic core of TDP-43 have demonstrated that oligomers greater than trimer are associ-ated with toxicity. Utilizing a joint pharmacophore space (JPS) method, potential drugs have been designed specifically for amyloid related diseases. These molecules were generated based on key chemical features necessary for blood brain permeability, low adverse side affect and target selectivity. Combining ion-mobility mass spectrometry and atomic force microscopy with the JPS computational method allows us to more efficiently evaluate a potential drug's efficacy in disrupting the development of putative toxic species. Results are presented that demonstrate the dissociation of higher order oligomers in the presence of these novel JPS generated inhibitors into smaller oligomer species. Additionally, FDA approved drugs for the treatment of ALS were also evaluated and demonstrated to maintain higher order oligomeric assemblies. Possible mechanisms for observed action of the JPS molecules are commented on.