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Principal Investigator: Weiwei Dang
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $160,000
Funding agency: National Institute on Aging
PROJECT SUMMARY
Many forms of human dementia are caused by aberrantly folded proteins and protein aggregates.
Overexpressing these disease proteins, such as α-synuclein and TBD-43, in the budding yeast Saccharomyces
cerevisiae, also causes cytotoxicity, allowing unbiased powerful genetic screens for modifiers that enhance or
repress toxicity. Hence, this single-celled eukaryotic model has been a powerful genetic tool for discovering
molecular pathways regulating human dementia caused by protein misfolding and aggregation, such as the
Parkinson’s disease and frontotemporal dementia.
Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and aggregated Tau proteins are a
major pathological hallmark of Alzheimer’s disease (AD), as well as other neurodegenerative disorders
collectively termed Tauopathies. Despite the strong clinical association, how wildtype human Tau proteins
become hyperphosphorylated and cytotoxic remains poorly understood. Distinguished from other protein
aggregates that cause dementia, overexpressing human Tau is well tolerated in the budding yeast with no
apparent growth phenotype, even though human tau proteins are also hyperphosphorylated and aggregated in
yeast cells. Hence, no yeast genetic screen for Tau toxicity modifiers has been performed thus far. Yet,
tremendous potential remains if Tau-induced cytotoxicity can be reproduced in the simple yeast model,
permitting unbiased screens to uncover the molecular pathways involved in tau toxicity and related diseases.
In a preliminary screen, we have identified several ORF deletion mutations that show toxicity when human
wildtype Tau (2N4R) is expressed. Interestingly, two of these mutant genes, THP1 and SAC3, encoding for
subunits of the evolutionarily conserved TREX2 complex, are involved in activating stress response gene
expression and mRNA export. Hence, we hypothesize that timely stress response at the transcription level
is necessary for yeast cells to antagonize the toxicity induced by misfolded Tau. It is also possible that
Tau proteins in thp1∆ and sac3∆ mutants adopt a cytotoxic conformation/state reminiscent of the situation of
Tau pathology in neurons. Indeed, our analysis of the NIAGADS database uncovered that AD-associated genetic
variants were found in four of the five subunits of the human TREX2 complex, making it one of the top 15 protein
complexes enriched for AD variants.
For this small pilot project, we will 1) investigate the cause of Tau toxicity in strains mutated for TREX2
subunits using a combination of genetics, genomics and biochemical approaches; 2) develop a set of tools that
can help establish a novel Tau toxicity model in the budding yeast, allowing future unbiased screens for genetic
modifiers of Tau toxicity.
Terms: <3' Repair Exonuclease 2><3-Prime Repair Exonuclease 2><AD dementia><Adopted><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amentia><Antibodies><Assay><Baker's Yeast><Bioassay><Biochemical><Biological Assay><Brewer's Yeast><Budding Yeast><Categories><Cell Body><Cells><Clinical><Collaborations><Complex><D-Galactose><Data><Data Bases><Databases><Defect><Degenerative Neurologic Disorders><Deletion Mutation><Dementia><Disease><Disorder><Drosophila><Drosophila genus><Drug Metabolic Detoxication><Drug Metabolic Detoxification><Endomycetales><Eukaryotic Cell><Expression Library><FRET><Flies><Fluorescence Resonance Energy Transfer><Frontal Temporal Dementia><Frontotemporal Dementia><Future><Förster Resonance Energy Transfer><Galactopyranose><Galactopyranoside><Galactose><Gene Expression><Gene Transcription><Gene variant><Generalized Growth><Genes><Genetic><Genetic Screening><Genetic Transcription><Genomics><Growth><Human><Immunoblotting><Letters><Lytotoxicity><MT-bound tau><Measures><Metabolic Drug Detoxications><Metabolism of Toxic Agents><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Microfluidics><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mutate><NAC precursor><Nature><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurofibrillary Tangles><Neurologic Degenerative Conditions><Neurons><ORFs><Open Reading Frames><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathology><Pathway interactions><Phenotype><Physiologic><Physiological><Pilot Projects><Primary Parkinsonism><Primary Senile Degenerative Dementia><Protein Coding Region><Proteins><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Repression><Role><S cerevisiae><S. cerevisiae><SNCA><SNCA protein><Saccharomyces cerevisiae><Saccharomycetales><Stress><TREX2><TREX2 gene><Tauopathies><Technology Transfer><Testing><Three Prime Repair Exonuclease 2><Tissue Growth><Toxic effect><Toxicities><Transcription><Validation><Variant><Variation><Western Blotting><Western Immunoblotting><Yeast Model System><Yeasts><a-syn><a-synuclein><aberrant folded protein><aberrant folded proteins><aberrant protein folding><abnormal folded protein><abnormal folded proteins><abnormal protein folding><abnormally aggregated tau protein><allele variant><allelic variant><alpha synuclein><alpha synuclein gene><alphaSP22><asyn><biological adaptation to stress><cell type><conformation><conformational><conformational state><conformationally><conformations><cytotoxic><cytotoxicity><data base><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><detection sensitivity><detoxification><differential expression><differentially expressed><filamentous tau inclusion><fluorescence imaging><fluorescent imaging><fly><front temporal dementia><frontal lobe dementia><frontotemporal lobar dementia><frontotemporal lobe degeneration associated with dementia><fruit fly><genetic variant><genomic variant><global gene expression><global transcription profile><insoluble aggregate><knock-down><knockdown><mRNA Export><microfluidic chip><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule bound tau><microtubule-bound tau><misfolded protein><misfolded proteins><model organism><mutant><neurodegenerative illness><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuronal><neuropathologic tau><neuropathological tau><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><ontogeny><overexpress><overexpression><p-tau><p-τ><paired helical filament of tau><pathologic protein folding><pathway><phospho-tau><phospho-τ><phosphorylated tau><pilot study><post-translational modification of tau><posttranslational modification of tau><primary degenerative dementia><protein aggregate><protein aggregation><protein blotting><protein complex><protein expression><protein misfolding><proteotoxic protein><proteotoxin><reaction; crisis><response><self-aggregate tau><senile dementia of the Alzheimer type><social role><stress response><stress; reaction><stressor><tangle><tau><tau PHF><tau Proteins><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau conformation><tau expression><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 phosphorylation><tau polymerization><tau posttranslational modification><tau-1><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><tool><transcriptional differences><transcriptome><transcriptome sequencing><transcriptomic sequencing><validations><yeast genetics><yeast model><µfluidic><α synuclein gene><α-syn><α-synuclein><τ Proteins><τ aggregation><τ conformation><τ expression><τ phosphorylation>