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Principal Investigator: Songi Han
Organization: UNIVERSITY OF CALIFORNIA SANTA BARBARA
Fiscal Year: 2024
Award: $711,751
Funding agency: National Institute on Aging
PROJECT SUMMARY
The bottleneck for tauopathy therapy development is the lack of validated tauopathy models, mouse, cell or in vitro.
This is reflected in the current reality that tauopathy-specific fibril structures solved by cryo-EM from post mortem
patient brain tissue have never been replicated outside a patient, i.e. not in a mouse, cell or in vitro. While the patient-
derived tauopathy fibrils offer critical goal posts, they are not in and of themselves viable therapeutic targets. For
example, the development of Positron Emission Tomography (PET) ligands to diagnose and track Alzheimer’s disease
(AD) or corticobasal degeneration (CBD) disease progression relies on screening small molecule binding to CBD- or
AD-phenotypic fibrils—the very construct that nobody knows how to build yet. There are many more factors to consider
for replicating the pathological pathway of tau aggregation, but replicating disease phenotypic tau fibrils is a minimal
and necessary requirement, and so far an unattained tool for therapy development. The major knowledge gap that
this proposal aims to close is the mechanism and tools to replicate tauopathy specific fibrils in vitro (Aim 1),
and the key cellular and molecular factors that initiate misfolding of tau in cell to disease phenotypic shapes
and facilitate aggregation (Aim 2). If we can successfully replicate any one tauopathy-phenotypic tau fold, or even
a part of a folded tau structure, such as a mini-hairpin fold of CBD or AD with seeding competency, it will have an
immediate impact on ongoing therapy developments, such as on the development of tauopathy-specific PET ligands,
antibodies and small molecule drugs. This team will employ an innovative set of structural biology tools encompassing
pulsed double electron-electron resonance (DEER), TEM and cryo-EM, as well as computational tools to focus on
capturing the full folding and aggregation pathway of the tau protein ensemble from its intrinsically disordered to
partially folded and fully converged fibril states. This team will concurrently use innovative cell biological tools with a
strong premise of the knowledge of a dedicated tau receptor and transporter that can enhance tau seeding by
endosomal escape and the knowledge that enhanced hydrophobicity of the local environment of tau is a potent factor
to initiate misfolding, aggregation and propagation. While discovering the defining property of a competent seed and
achieving shape propagation with seeds developed in this proposal will be a breakthrough, independent of this
success, we will have developed experimental and computational tools to evaluate whether seeded shape
propagation has occurred, or whether all, part, or none of the shape propagates. To have the tools to evaluate the
mechanism of shape propagation will be a game changer. The lack of progress in closing the above-described
knowledge gap is not due to a lack of investment by top notch laboratories around the world, but due to shortcomings
of existing concepts and tools. Han and Kosik, together with Shea, will rely on the convergence of their respective
fields and investing concerted effort using innovative tools to address long-standing questions in tauopathy research.
Terms: <AD dementia><AD pathology><Address><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Antibodies><Autopsy><Binding><Biological><Body Tissues><Brain><Brain Nervous System><Bypass><Cell Body><Cell Line><CellLine><Cells><Cellular Inclusions><Cellular biology><Chemistry><Competence><Computational toolkit><Corticodentatonigral degeneration with neuronal achromasia><Cromolyn Sodium><Cytoplasm><Dedications><Detection><Development><Diagnosis><Diagnostic><Disease><Disease Progression><Disodium Cromoglycate><Disorder><Drugs><Electrons><Encephalon><Endosomes><Environment><Event><Feedback><Fostering><Generations><Genetic Alteration><Genetic Change><Genetic defect><Goals><Hand><Heparin><Heparinic Acid><Human><Hydrophobic Surfaces><Hydrophobicity><In Vitro><Inclusion Bodies><Induced pluripotent stem cell derived human neuron><Initiation Factors><Intal><Investments><Knowledge><Laboratories><Learning><Ligands><Light><Lipids><Liquid substance><Location><MT-bound tau><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Morphology><Murine><Mus><Mutation><Nasalcrom><Negative Beta Particle><Negatrons><Neurofibrillary Tangles><Organoids><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathologic><Pathology><Pathway interactions><Patients><Peptide Initiation Factors><Persons><Pharmaceutical Preparations><Phase><Phenotype><Photoradiation><Physiologic pulse><Play><Population><Porosity><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Progressive Supranuclear Ophthalmoplegia><Progressive Supranuclear Palsy><Property><Proxy><Pulse><Rad.-PET><Receptor Protein><Receptosomes><Research><Shapes><Sodium Cromoglycate><Steele-Richardson-Olszewski Disease><Steele-Richardson-Olszewski Syndrome><Strains Cell Lines><Structure><System><Tauopathies><Testing><Therapeutic><Tissues><Translation Initiation Factor><Translational Initiation Factor><Transmission Electron Microscopy><Travel><Work><abnormally aggregated tau protein><aggregation pathway><biologic><brain tissue><cell biology><clinical phenotype><cofactor><computational toolbox><computational tools><computational toolset><computerized tools><cortical basal degeneration><cortico-basal degeneration><corticobasal degeneration><cryogenics><cultured cell line><develop therapy><developmental><diagnostic ability><diagnostic capability><diagnostic power><diagnostic utility><diagnostic value><disease phenotype><drug/agent><experiment><experimental research><experimental study><experiments><filamentous tau inclusion><fluid><genome mutation><hands><hiPSC-derived neurons><human iPSC-derived sensory neuron><iPSC-derived human neuron><innovate><innovation><innovative><intervention development><liquid><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><necropsy><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuropathologic tau><neuropathological tau><notch><notch protein><notch receptors><paired helical filament of tau><pathway><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><postmortem><primary degenerative dementia><protein folding><receptor><screening><screenings><self assembly><self-aggregate tau><senile dementia of the Alzheimer type><small molecule><structural biology><success><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau polymerization><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><therapeutic target><therapy development><tool><treatment development><uptake><τ Proteins><τ aggregation>