A wide range of neurodegenerative diseases affect the central nervous system (CNS) and lead to impaired sensory, motor, and cognitive processes. This impairment can lead to permanent damage to neuronal health and eventual neuronal death. The complex disease pathophysiology and poorly studied underlying mechanisms have led to an increase in therapeutic efforts, which have historically been proven to be difficult. Proteolytic Targeted Chimera (PROTAC®) protein degraders open up new and exciting opportunities for degrading disease-causing mutants and protein aggregates, starting with tauopathies and synucleinopathies. Some hallmarks of the new generation of PROTACs are improved pharmacology to cross the blood-brain barrier (BBB), increased catalytic activity to break down aggregates to prevent diffusion to healthy neurons, and the ability to adapt to new delivery mechanisms. There is ample evidence that large protein aggregates are proteasome-resistant, so PROTACs that selectively drive degradation through the autophagosomal mechanism can significantly improve therapeutic outcomes. It is of great significance to study novel E3 ligases compared to traditional E3 ligases to generate polyubiquitin chains that can promote both proteasomal and lysosomal degradation. Lifesensors has developed custom high-throughput assays to study PROTAC-mediated ubiquitination and degradation of protein aggregates to provide mechanistic insights that help chemists design reliable SARs.