UC San Diego

Neurodegenerative diseases such as Alzheimer’s disease (AD) are becoming more prevalent as the average human lifespan increases. Despite decades of research, no therapeutics exist that can slow the progress of AD. One of the hallmark symptoms that best correlates with symptoms of AD is synapse loss at the cellular level. Ethylene glycol (EG) analogs of benzothiazole aniline (BTA) improve memory and learning in mice by increasing the number of postsynaptic connection sites or dendritic spines in neurons. These compounds interact with the protein Fascin1. Through a combination of knockdown and overexpression studies, I show that Fascin1 levels affect dendritic spine density. Using tandem mass tag mass spectrometry pulldowns using human brain cortex lysate, I identify Fascin1-protein interactions that change in the presence of BTA-EG4 and BTA-EG6. I identify changes in focal adhesions, or sites at which the cell creates an attachment to the extracellular matrix, by immunofluorescence as a method by which BTA-EG4 and BTA-EG6 may be impacting dendritic spine density. I also provide structural evidence for the binding pocket between Fascin1 and BTA-EG6 using solution protein nuclear magnetic resonance (NMR) and site-directed mutagenesis.