Project 1
Quantitative Mapping of PTMs of soluble (monomers, oligomers) and insoluble alpha-synuclein from selected brain regions and cell types as a function of disease progression and in familial α-synucleinopathies.
Lead PI
- Prof. Hilal A. Lashuel — Weill Cornell Medicine–Qatar
Co-Lead PIs
- Prof. Glenda Halliday — University of Sydney, Australia
- Prof. Chao Peng — UCLA, USA
A collaboration with
- Prof. Judith Steen, Mass General Hospital and Harvard Medical School, USA
- Prof. Matthias Mann, Max Planck Institute of Biochemistry, Munich, Germany,
- Prof. Thomas Beach, Mayo Clinic, USA.
Project 2
Investigating the Role of Neuron-Glia Crosstalk in Regulating Alpha-Synuclein Pathology Formation and Clearance in a Novel Triculture Model of Lewy Body Maturation and Neurodegeneration
Led by the Lashuel Laboratory (Weill Cornell Medicine-Qatar) with Stanford University (Drs. Abu-Remaileh, Wernig, Bassik) and Arvinas
Lead PI
- Prof. Hilal A. Lashuel — Weill Cornell Medicine–Qatar
Co-Lead PIs
- Stanford University (Prof. Monther Abu-Remaileh, Prof. Marius Wernig, and Prof. Michael Bassik)
Background
Parkinson's disease (PD) is characterized by alpha-synuclein (aSyn) aggregation, Lewy body formation, and neurodegeneration, with mounting evidence pointing to lysosomal dysfunction and impaired clearance as central contributors to pathogenesis. Neuron-glia interactions shape these processes, where astrocytes and microglia can promote clearance or amplify inflammation. However, how these interactions regulate the balance between protective and harmful pathways remains unclear, and current models fail to capture their complexity across different brain cell types.
Project Description
This project leverages a novel human iPSC-derived triculture system of dopaminergic neurons, astrocytes, and microglia that recapitulates the full spectrum of aSyn pathology formation within a physiologically relevant environment. The collaboration brings together expertise in chemical biology and neurodegeneration (Lashuel Lab), lysosomal biology (Abu-Remaileh), iPSC-derived neuronal models (Wernig), functional genomics and CRISPR screens (Bassik), and targeted protein degradation (Arvinas).
Our integrated research strategy encompasses four objectives: (1) dissecting molecular and genetic determinants of aSyn clearance across brain cell types, examining how aggregation state, sequence, and PD-linked lysosomal mutations affect degradation using forward genetics and lysosome profiling; (2) exploring how neuron-glia interactions influence aSyn aggregation, propagation, and toxicity using both seeding-based approaches and de novo aggregation systems; (3) investigating the interplay between lysosomal dysfunction and neuroinflammation by introducing PD-linked mutations into specific cell types and employing single-cell RNA-seq, multiplex cytokine profiling, and high-content imaging; and (4) evaluating targeted degradation strategies, including PROTACs and BMP lipid boosters, to clear aSyn aggregates while preserving physiological function.
Impact
This project will advance understanding of cell-type-specific mechanisms governing aSyn clearance and pathology formation, defining the most disease-relevant toxic species and their impact on neuronal and glial cells. By combining cutting-edge cellular modeling, genetic screens, and targeted degraders, we aim to identify druggable pathways for enhancing lysosomal function, clearing pathogenic aSyn species, protect against neurodegeneration. and slow down or prevent pathology spreading and PD progression.
Expected Impact
By combining world-class expertise in neurodegenerative research and next-generation proteomics, this project aims to decipher the post-translational modification code of aSyn proteins in both health and neurodegenerative disease. The platform will reveal the complete landscape of aSyn proteoform diversity and uncover fundamental mechanisms of PD progression. Most importantly, this work will enable development of novel, highly specific proteoform-based biomarkers that could revolutionize early diagnosis, improve patient stratification, and enhance disease monitoring. The successful development of this single-molecule assay represents a significant leap forward in democratizing access to the proteome and enabling fundamental advancements in understanding and treating Parkinson's disease and related synucleinopathies affecting millions worldwide.