Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Tauopathies are a group of heterogeneous neurodegenerative diseases characterized by pathological aggregation of tau protein in the brain. The most common primary tauopathy, progressive supranuclear palsy (PSP), is identified clinically by progressive parkinsonism with supranuclear gaze paralysis, cognitive dysfunction, behavioral changes, and other neurological deficits. Neuropathologically, PSP has a constellation of features including morphologically distinct tufted astrocytes (TA). Astrocytes normally do not contain significant levels of tau suggesting that TA play an important, but unknown, pathological role in PSP. The majority of PSP cases are sporadic. Genome wide association studies have identified common variants associated with PSP risk in EIF2AK3, which encodes an endoplasmic reticulum (ER) stress sensor critical for the unfolded protein response (UPR). There is evidence for a pathogenic association between ER stress in astrocytes and tau accumulation in PSP, but to test candidate molecular mechanisms there is a critical need for a model system that recapitulates the cellular environment of the human brain and retains the genetic complexity of human disease. Developing human induced pluripotent stem cell (iPSC)-derived models generated from PSP patients will be a powerful tool to characterize molecular drivers of sporadic tauopathy. We hypothesize that UPR activation in astrocytes drives neurodegeneration and plays a key role in sporadic PSP. In our first aim, we will correlate UPR activation with astrocyte pathology and degeneration in human post-mortem brain tissue. Autopsy-confirmed PSP brain tissue from our large collection will be stained, imaged, and analyzed for p-tau distribution and UPR colocalization using innovative quantitative approaches. In the second aim, we will test the hypothesis that PSP neurons and astrocytes are highly vulnerable to tau pathology, and that UPR activation in PSP astrocytes increases cell vulnerability. To accomplish this aim, we will create patient iPSC-derived monolayer neurons and astrocytes and directly measure molecular changes and cell vulnerability by pharmacological manipulation of the UPR. Lastly, we will determine the extent to which UPR activation in astrocytes increases the production of toxic tau species and cell vulnerability in an iPSC-derived organoid model of sporadic PSP. This aim will explore molecular perturbations in different cell populations that contribute to the development of tau pathology in a 3-D cellular environment that recapitulates the complex neuronal-astrocyte interactions that occur in human brain tissue. These findings will be validated in paired autopsy brain tissue from the same donor. In summary, the clinical-translational research performed in this study will generate patient- derived iPSC models that retain a disease-relevant genomic background and reveal candidate pathways that are disrupted early in sporadic PSP.
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