How do different GBA mutation types respond to TFEB activation in patient-derived neurons?

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Description

The debate mentioned testing different GBA mutations but provided no mutation-specific data. This personalized medicine question is critical for patient stratification and predicting therapeutic response.

Source: Debate session sess_SDA-2026-04-10-gba-pd (Analysis: gba-pd)

Resolution criteria

Gap closes when: (1) iPSC-derived neurons from patients carrying at least 3 GBA mutation types (e.g., N370S, L444P, and a null allele) are treated with a TFEB activator and compared for GCase activity recovery (fluorescent substrate assay), glucosylceramide clearance (LC-MS/MS), and alpha-synuclein burden (ELISA); and (2) statistical analysis demonstrates significant mutation-specific differences in response magnitude (ANOVA FDR < 0.05); and (3) the results are used to derive a mutation-response model predicting responder vs. non-responder status with AUC >= 0.75 on held-out samples. Deliverable: comparative iPSC dataset with GCase activity, lipidomics, and response model in a public repository.

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