Novel Approaches for Tau PROTAC Drug Discovery Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) are a group of neurodegenerative diseases characterized by the pathological accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), or aggregates, within neurons and glia of affected brain regions, leading to cell death. Several approaches to remove aggregates of pathogenic tau have failed, including antibody therapy. Novel approaches to remove aggregated proteins are desired. Targeted protein degradation by PROteolysis TArgeting Chimeras (PROTACs) has emerged as novel therapeutic modality. PROTACs are heterobifunctional small molecules that simultaneously bind to a target protein and a ubiquitin E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present a new opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. PROTAC drugs offer many advantages, such as: 1) target can be selectively degraded with catalytic specificity; 2) weak binders can be converted into selective PROTAC drugs; 3) overexpressed or mutant targets can be degraded; and 4) limited target engagement can lead to maximal degradation. Although most misfolded and aggregated proteins in the human proteome can be degraded by proteasomal system, some native and mutant proteins prone to aggregation, such as tau oligomers are resistant to all known proteolytic pathways thus subject to autophagic or lysosomal pathway. Development of PROTACs that can efficiently degrade pathogenic tau aggregates is an attractive and breakthrough therapy for AD and FTD. No one, industry or academia has shown credible data for tau PROTACs to succeed in the clinic. Traditional methods for PROTAC analysis, western blot or reporter gene analysis are time consuming, cumbersome, and prone to artifacts. In this proposal we describe a high throughput method for rapid development of tau PROTACs. Development of PROTACs that promote tau degradation by lysosomal/autophagic mechanism is challenging. This grant proposes strategies to screening different E3 ubiquitin ligases for tau PROTAC that will remove pathogenic (monomeric) as well as aggregates through autophagic mechanism. Goal of the project is to establish rules that govern pathogenic tau degradations, such as poly-ubiquitin signatures conjugated on tau aggregates to differentiate proteasomal vs lysosomal degradation. Development of the technology that degrades tau aggregates can be directly applied to Parkinson’s disease, Huntingdon disease and Amyotrophic Lateral Scleroses.