top of page

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

  • Our lab is at the forefront of uncovering the pathways facilitating the intercellular transmission of pathological α-synuclein (α-syn) 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.

  • A key finding is that internalized pathological α-syn 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-syn transmission and neurodegeneration.

Current Projects:

  • Dissecting the LAG3-APLP1 uptake pathways for therapeutic targeting

  • Interrogating the PARP1/PAR pathway in spreading and identifying inhibitors

LAG3.jpg

​Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3 (Science 2016)

​

  • We identified LAG3, APLP1, and Neurexins as pathogenic α-syn receptors.

  • All these receptors exhibit preferential binding with α-syn preformed fibrils (PFF) compared to α-syn monomer.

  • Depletion of LAG3 or inhibition of LAG3 by anti-LAG3 can inhibit the neuronal uptake of α-syn PFF, subsequent pathology propagation, and neurotoxicity, and alleviate behavioral deficits.

image.png

Mechanistic basis for receptor-mediated pathological α-synuclein fibril cell-to-cell transmission in Parkinson's disease: Lag3 binds with α-syn PFF but not monomer (PNAS 2021)

  • Formation of α-syn fibrils disrupts intramolecular interactions with the C-terminus, exposing and condensing the C-terminus on the fibril surface, increasing binding affinity to the receptors.

  • α-Syn serine 129 phosphorylated (pS129), a pathological α-syn modification, further enhances fibril binding to receptors.

  • pS129 fibrils showed higher cellular internalization, seeding ability, and induced α-syn pathology in transgenic mice.

image.png

Aplp1 interacts with Lag3 to facilitate the transmission of pathologic α-syn (Nat Comm 2024)

  • APLP1 is an independent receptor of pathological α-syn, but can also interact with LAG3, facilitating the binding, internalization, transmission, and toxicity of .

  • Deleting both APLP1 and LAG3 can reduce up to 95% α-syn pathology, and eliminate the loss of dopaminergic neurons and related behavioral deficits induced by α-syn PFFs in experimental models.

  • Anti-LAG3 antibodies prevent the internalization of α-syn PFFs by disrupting the APLP1-LAG3 interaction, and block the neurodegeneration induced by α-syn PFFs in vivo.

image.png

LAG3 Facilitates Pathological Tau Neuron-to-Neuron Transmission (Adv Sci 2024, back cover)

  • Lag3 is a cell surface receptor that binds specifically to the pathological tau PFF, but not to tau monomer.

  • Deletion or inhibition of Lag3 in neurons significantly reduces the internalization of tau PFF, subsequent tau propagation, and neuron-to-neuron transmission of tau pathology.

  • In mouse models, deletion of neuronal Lag3 attenuates the propagation of tau pathology and behavioral deficits induced by injection of tau PFF in the brain.

PAR.jpg

Poly (ADP-ribose) drives pathologic α-syn neurodegeneration in Parkinson’s disease (Science 2018)

  • This study reveals that pathologic α-syn activates poly(ADP) polymerase-1 (PARP-1), triggering PAR generation.

  • PAR generation accelerates the formation of pathologic α-syn, resulting in cell death via parthanatos (a type of cell death).

  • Inhibition of PARP-1 either pharmacologically or genetically prevents the toxicity induced by pathologic α-syn.

  • A feed-forward loop is observed where PAR further converts pathologic α-syn into a more toxic strain.

  • Increased levels of PAR are found in the cerebrospinal fluid and brains of PD patients, suggesting PARP activation's role in PD pathogenesis.

Nanotechnology-Based Interventions Against Pathogenic Seed Transmission

image.png
image.png

  • 2. Developing Therapeutics to Block Prion-like Protein Propagation

  • Building on our mechanistic insights, we are actively pursuing therapeutic strategies to halt the propagation of pathological α-synuclein and tau conformers:

  • Generating and evaluating nanobodies that disrupt prion-like protein aggregation and intercellular transmission (Nat Comm 2022)

  • Leveraging nanozymes to scavenge reactive oxygen species implicated in prion pathology (Nano Today 2021)

  • Through our multidisciplinary approach, combining molecular biology, bioengineering, and nanomedicine, we aim to elucidate key mechanisms and deliver effective therapeutics for prion proteinopathies.

bottom of page