Kenneth Kosik
University of California-Santa Barbara, CA·Neuroscience
In Alzheimer's disease, Parkinson's disease and related disorders, proteins lose their normal shape and stack into rigid fibers called amyloids that build up and disrupt nerve cells. Each disease appears to produce its own distinct fiber shape.
- Fields
Neuroscience
Biochemistry
Biophysics
- Topics
tau
amyloid
protein misfolding
- Grants
- 2 known grants, through Jul 2027
What they work on
- Determine the mechanism and build the tools to replicate tauopathy-specific tau fibrils in vitro, including Alzheimer's and corticobasal degeneration folds, so that PET imaging ligands, antibodies and small molecules can be screened against real disease structures.
- Map the complete folding and aggregation pathway of tau, from intrinsically disordered to partially folded to fibril, using pulsed double electron-electron resonance spectroscopy, transmission and cryo-electron microscopy, and computational modeling.
- Identify the cellular and molecular factors that initiate tau misfolding in cells, testing the roles of a dedicated tau receptor and transporter that enhance seeding through endosomal escape and of increased hydrophobicity around tau.
- Develop experimental and computational tests of whether a seed propagates its shape, determining whether all, part, or none of a fibril fold is transmitted to newly recruited tau.
- Assess the translation potential of an artificial intelligence and physics-based platform that designs antibodies, nanobodies and peptides against amyloid surfaces, through experiential learning and interviews across the industry ecosystem.
- Evaluate the platform's design-test loop, in which engineered mini-amyloids mimicking patient filaments are screened by high-throughput yeast display and the results refine predictions for targets including Alzheimer's, Parkinson's and transthyretin amyloidosis.
More about the research
Researchers can image those shapes in tissue taken from patients after death, but nobody has been able to recreate them in a dish, in a cell, or in a mouse. That gap is a bottleneck: drugs, antibodies and brain-imaging tracers all need the right target structure to screen against. These two projects approach the problem from complementary directions, one working out how the tau protein converts from a normal, floppy molecule into disease-shaped fibers, the other assessing whether a computational platform for designing molecules that stick to amyloid surfaces can be translated into real products.
Why it matters
Amyloid diseases affect millions of people, and progress on treatments and diagnostics has been slowed because the disease-specific protein structures cannot be made outside patients. Recreating those structures, and designing antibodies or small molecules that recognize them, could support better PET imaging tracers for tracking Alzheimer's and corticobasal degeneration and could speed earlier detection and more selective therapies for neurodegenerative and systemic amyloid conditions.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
David Eisenberg
University of California-Los Angeles, CA·Biochemistry
Discover safe Tau disaggregants through repeated cycles of solving structures of Alzheimer's brain Tau fibrils bound to compounds and screening new compounds that fit the drug-binding site.
Allison L Kraus
Case Western Reserve University, OH·Neuroscience
Define the age of onset, amount, brain location and chemical variety of tau seeds in diseased, normal, young and older human brains, using RT-QuIC seed amplification assays specific to 3R, 4R and 3R/4R tau.
Luke Berchowitz
Columbia University, NY·Biochemistry
Determine the molecular mechanism by which multi-site phosphorylation rapidly reverses amyloid-like Rim4 into oligomers and monomers at the onset of meiosis II in budding yeast.
The school
University of California-Santa Barbara: 17 labs on PI Pages, $303M a year on research, 403 research doctorates a year.
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