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PD Functional Genomics

Prior to the launch of the ASAP initiative, Parkinson’s disease research primarily centered on mechanisms involving known risk genes and disrupted pathogenic processes. Genetic advancements over the past decade have shifted focus from single genes to broader genomic changes, resulting in a greater need to better understand effects on organelle and cellular function within the context of the disrupted pathogenic processes. Researchers within the PD Functional Genomics theme use innovative approaches to uncover mechanisms contributing to PD pathogenesis and progression. The research focuses on two major areas:

  • Conducting unbiased analyses of human datasets and models to identify novel targets and mechanisms.
  • Investigating the functional impact of known risk genes (e.g., SNCA, GBA1, LRRK2, PRKN, PINK1) and pathogenic pathways (e.g., mitophagy, lysosomal dysregulation) on disease progression and heterogeneity.

Highlights

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Single cell eQTL mapping reveals convergent glial–neuronal risk architecture in Parkinson’s disease

Population-scale, disease-context aware meta single-nucleus eQTLs mapping (N = 1,197) in nine cell types from cortex and substantia nigra identifies 125 risk genes and cell types for PD GWAS signals.

CREsted: modeling genomic and synthetic cell-type-specific enhancers across tissues and species

CREsted, a sequence-based deep learning model, analyzes genomic regulatory code, decodes enhancer grammar, and designs synthetic enhancers. It preprocesses single-cell data, models chromatin accessibility, and compares cell states across tissues.

A druggable ATP13A3–antizyme switch controls adaptive polyamine uptake in cancer

Cellular polyamine depletion for cancer treatment is hindered by compensatory uptake. ATP13A3, not ATP13A2, is the key polyamine importer affected by DFMO. Antizyme inhibits uptake by ATP13A3, suggesting a targetable strategy for cancer therapy.

Cryo-EM structure of soluble VPS13C suggests its regulation by a conformational switch and by calmodulin

Structural studies of the Parkinson's protein VPS13C provide a molecular basis for understanding its function and regulation.

Our Teams

The focus across these teams will be to unravel the biology underlying genetic mutations associated with Parkinson’s disease.