UC Santa Barbara

TAR DNA-binding protein of 43kDa (TDP-43) aggregates are a salient feature for amyotrophic lateral sclerosis (ALS), observed in over 95% of ALS patients. TDP-43 aggregates are also found in 45% of frontotemporal dementia (FTD) patients and have been implicated in a variety of other neurodegenerative diseases including Alzheimer’s disease (AD), where TDP-43 is observed in 30-70% of AD patients and correlated to more severe cognitive impairment. With an anticipated growth in the most susceptible demographic, projections predict neurodegenerative diseases will rise from the 3rd leading cause of death, passing cancer, and falling second to cardiovascular by 2050, potentially affecting 15 million people in the United States alone. Currently there are no cures for ALS, FTD or AD. Consequently, TDP-43 proteinaceous inclusions are a critical target in all three of these diseases and others as well.

Utilizing ion mobility mass spectrometry we were able to 1) characterize the aggregation mechanism for TDP-43 and SOD1 peptides and selected mutations; 2) in collaboration with Ambuj Singh and Acelot, evaluate the therapeutic affects of their JPS-trained small molecules on known aggregation and 3) investigate aggregation across different protein systems to gain insight to how TDP-43 may be involved in AD. This work elucidates potential cytotoxic structures, demonstrates the versatility of IM-MS as a screening method for disease target specificity, and supports evidence for cross protein system aggregation that may have significant implications across a range of disorders.