How does protein misfolding perturb the physiology of and interaction between distinct cell types within the nervous system?
How does the physiologic function of proteins relate to the toxicity that results when these proteins misfold?
Do distinct forms (or “strains”) of misfolded proteins cause pathology in different ways?
How can we best exploit our understanding of perturbed proteostasis for clinical translation – i) better personalized stem cell models; ii) better biomarkers; iii) patient-specific therapies
Tissue Engineering Approaches (reprogramming, genome editing, differentiation) to create stem cell-derived glial and neuronal co-culture systems and mini-brain organoids to model neurodegenerative proteinopathies.
Systems biology approaches (Picture 1) that encompass
Unbiased genetic screens (multiplexed CRISPR-Cas9 genome editing) to identify the key genes and processes that contribute to the toxic consequences of protein misfolding.
Mapping the protein interaction network of misfolding proteins (Ascorbate peroxidase [APEX]-based in situ labeling, membrane-2-hybrid interaction mapping).
Computational tools (Steinernet prize-collecting algorithm among others) that integrate these data to map the consequences of protein misfolding at proteome-scale.
Mechanistic studies to test specific hypotheses arising from our systematic genetic and protein interaction networks.
Systems Biology approaches lay the foundation for more detailed mechanistic and therapeutic studies in patient-derived neurons and glial cells.
Our initial focus is on alpha-synuclein, a protein that misfolds in Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA).We are particularly interested in alpha-synuclein function and toxicity within neurons and oligodendrocytes. Mechanistic studies will initially focus on perturbed mRNA metabolism in synucleinopathy, a relationship we have recently uncovered. We have also recently begun to investigate proteins that aggregate in spinocerebellar ataxias and related disorders
Among other funding sources, current funding is generously provided through federal grants (NIH R01, NIH R21, DOD), investigator-based awards to Vik Khurana (he is a New York Stem Cell Foundation Robertson Stem Cell Investigator and George Cotzias Fellow of the American Parkinson Disease Association), the Brigham and Women’s Research Institute, the National Ataxia Foundation, the MSA Coalition, an Aligning Science Across Parkinson’s award, and through the Ken Griffin award of the Michael J. Fox Foundation.