Abstract
Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas. Positron emission tomography (PET) tracers that bind to pathological tau are used in diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET-probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01-175 was designed to engage both tau and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, with minimal effect on tau from neurons of healthy controls, indicating specificity for disease-relevant forms. QC-01-175 also rescued stress vulnerability in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.
Highlights
Tauopathies, such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD), are a group of neurodegenerative diseases characterized by the pathologicalSilva et al eLife 2019;8:e45457
Through iterative design and testing in vitro and in ex vivo human neuronal cells, where each module element played a role in tau degradation efficacy, we identified the lead compound QC-01–175 (Figure 1C–II)
In this in vitro format, weaker binding was observed compared to PE859 (Figure 1—figure supplement 1A), QC-01–175 was able to bind to immobilized, soluble forms of WT (KD1.2 mM), A152T (KD1.7 mM) and P301L (KD2.5 mM) within the same order of magnitude as the control T807 (KD1.8 mM, 2.1 mM and 1.7 mM, respectively) (Figure 1E, Figure 1—figure supplement 1A–B III, VI)
Summary
Tauopathies, such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD), are a group of neurodegenerative diseases characterized by the pathological. Biochemistry and Chemical Biology Neuroscience accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), within neurons and glia of affected brain regions, leading to cell death (Kosik et al, 1989; Morris et al, 2011; Cruts and Van Broeckhoven, 2015; Ghetti et al, 2015; Neumann et al, 2015; Olney et al, 2017; Goedert, 2004). Tauopathies can be either sporadic or inherited as autosomal dominant disease when caused by mutations in the MAPT gene encoding the microtubule-associated protein tau. FTD is the most common form of dementia in individuals under 60 years of age, affecting approximately 60,000 individuals in the USA alone, with an economic burden that is nearly twice that reported for AD (Galvin et al, 2017). There are currently no effective disease-modifying therapies, highlighting an urgent unmet need
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
