Does TFEB activation directly restore mutant GBA enzyme activity or only enhance lysosomal biogenesis?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

90%

Importance

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Tractability

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Market price

50%

Description

The debate identified this as a critical mechanistic gap - TFEB may increase lysosomal volume without addressing the fundamental GBA enzyme defect. This distinction is essential for determining therapeutic efficacy and predicting which GBA mutations would respond.

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

Resolution criteria

Resolved when an isogenic iPSC-derived neuron model (GBA1 N370S or L444P vs corrected, >=3 independent clones) treated with a TFEB activator demonstrates: (a) GBA enzyme activity (4-MUG fluorimetric assay) change <=15% versus vehicle-treated mutant cells (showing TFEB does NOT directly restore GBA activity), AND (b) lysosomal volume increase >=40% (LysoTracker or Lamp1 immunostaining). Alternatively, >=30% GBA activity rescue qualifies as direct contribution evidence. A mechanistic rescue experiment using TFEB overexpression (AAV-TFEB, >=5-fold mRNA induction) is required. Deliverable: raw assay data in Zenodo; KG mechanism edge TFEB->GBA_activity disambiguated with ‘direct’ or ‘indirect’ tag.

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