Opportunities and Challenges in Phenotypic Screening for Neurodegenerative Disease Research

Toxic misfolded proteins potentially underly many neurodegenerative diseases, but individual targets which regulate these proteins and their downstream detrimental effects are often unknown. Phenotypic screening is an unbiased method to screen for novel targets and therapeutic molecules and span the range from primitive model organisms such as Sacchaomyces cerevisiae, which allow for high-throughput screening to patient-derived cell-lines that have a close connection to the disease biology but are limited in screening capacity. This perspective will review current phenotypic models, as well as the chemical screening strategies most often employed. Advances in in 3D cell cultures, high-content screens, robotic microscopy, CRISPR screening, and use of machine learning methods to process the enormous amount of data generated by these screens are certain to change the paradigm for phenotypic screening and will be discussed.