Elucidating the Prion-like Propagation and Neurodegenerative Mechanisms of α-Synuclein and Tau Seeds
Research Directions
1. Elucidating Prion-like Protein Cell-to-Cell Spreading Mechanisms
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Our lab is at the forefront of uncovering the pathways facilitating the intercellular transmission of pathological α-synuclein and tau, the prion-like proteins implicated in Parkinson's and Alzheimer's diseases. We have identified several transmembrane proteins, including lymphocyte activation gene-3 (LAG3), amyloid precursor-like protein 1 (APLP1), and neurexins, that specifically bind and internalize these disease-associated protein species.
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A key finding is that internalized pathological α-synuclein triggers PARP-1 activation and PAR polymer accumulation, converting it into a highly toxic strain that accelerates neurotoxicity. Remarkably, depleting or inhibiting PARP-1 substantially impedes α-synuclein transmission and neurodegeneration.
Current Projects:
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Dissecting the LAG3-APLP1 uptake pathways for therapeutic targeting (Science 2016; PNAS 2021; Adv Sci 2024; BioRxiv)
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Interrogating the PARP1/PAR pathway in spreading and identifying inhibitors (Science 2018)
Nanotechnology-Based Interventions Against Pathogenic Seed Transmission
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2. Developing Therapeutics to Block Prion-like Protein Propagation
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Building on our mechanistic insights, we are actively pursuing therapeutic strategies to halt the propagation of pathological α-synuclein and tau conformers:
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Generating and evaluating nanobodies that disrupt prion-like protein aggregation and intercellular transmission (Nat Comm 2022)
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Leveraging nanozymes to scavenge reactive oxygen species implicated in prion pathology (Nano Today 2021)
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Through our multidisciplinary approach, combining molecular biology, bioengineering, and nanomedicine, we aim to elucidate key mechanisms and deliver effective therapeutics for prion proteinopathies.