How do tissue-specific chaperone networks determine differential vulnerability to the same protein misfolding variant?

The debate identified chaperone system differences as a key mechanism but failed to establish which specific chaperone components drive tissue selectivity. Understanding these networks is essential for developing tissue-targeted protein folding therapies.

Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062222-b5f44522 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062222-b5f44522)

Gap closes when: (1) A proteomics study comparing chaperone network compositions across at least three CNS cell types (neurons, astrocytes, oligodendrocytes) identifies >=5 chaperone components with >= 2-fold expression differences between vulnerable and resistant cell types; and (2) siRNA/CRISPR knockdown of the top candidate chaperones in iPSC-derived neurons and astrocytes reproduces >=30% differential aggregation of the misfolding-prone protein; and (3) results are replicated in at least one independent in vivo model (mouse or human postmortem tissue). Accepted deliverable: peer-reviewed publication or preprint with raw proteomics and aggregation quantification data publicly deposited.