TauSeeK: Disease Specific Tau Protein Fibrils & Seeding Proteins

NU2024-139

INVENTORS
Austin Dubose 
Michael Vigers
Andrew Longhini
Vishnu Vijayan
Kenneth Kosik
Sam Lobo
Peter C. Ryffel
Songi Han*

SHORT DESCRIPTION
Compositions, kits, and methods for generating synthetic miniature tau peptides and fibrils, and synthetic full-length pathogenic tau fibrils.

BACKGROUND
A major hallmark of several neurodegenerative diseases, such as Alzheimer’s, is the aggregation of the protein tau into fibrils. Mechanistic research on tau aggregation and the development of drugs and diagnostic agents targeting tau fibrils has traditionally been hampered by the fact that 3D tau conformations observed in different tauopathies are difficult to recreate in vitro. Mechanisms of pathogenic tau fibril formation are complex and dependent on factors such as the proteoform of tau monomer substrate (sequence, mutation, post-translational modification), cofactors, and aggregation conditions. Currently available synthetic tau protein fibrils are not adequately disease-specific, come pre-formed thus preventing the study of aggregation properties, or do not provide reproducible fibril formation. 

ABSTRACT
Northwestern inventors have developed a new way for researchers to generate synthetic tau protein fibrils that mimic pathological tau fibrils in various human tauopathies. The technology, TauSeek, involves compositions consisting of miniature tau peptides encompassing a critical fibril-inducing fold that are designed to incorporate different tau variants and post-translational modifications. The miniature tau peptides aggregate together under controlled conditions to form miniature tau fibrils with defined conformations capable of active seeding. Miniature tau fibrils then template full-length pathogenic tau fibrils and enforce conformations found in pathogenic tau aggregates. Also provided are methods and kits for generating the same. TauSeek can be used broadly for basic research, biomarker development, or drug discovery and screening.

APPLICATIONS

• Mechanistic study of tau fibril growth
• Biophysical characterization of tau aggregates
• Discovery and screening of drugs and diagnostics targeting tau 

ADVANTAGES 

• Reproducible and consistent generation of tau aggregates
• Easily tailored to disease-specific tau conformations
• No synthetic biology expertise required

PUBLICATIONS
Michael P. Vigers, and Songi Han et al. Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement. bioRXiV, Nov 28, 2023.

IP STATUS
A provisional patent application has been filed

Simplified workflow for full-length tau aggregation using TauSeek