ZCCHC17 modulates neuronal RNA splicing and supports cognitive resilience in Alzheimer’s disease

ZCCHC17 is a zinc-finger protein previously identified as a regulator of synaptic gene expression which becomes dysfunctional in Alzheimer’s disease. Here, we further investigate the function of ZCCHC17. Co-immunoprecipitation of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17’s binding partners are enriched for RNA splicing proteins. ZCCHC17 knockdown results in widespread RNA splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression positively correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden.  Furthermore, a majority of ZCCHC17 interactors also co-IP with known tau interactors, and we find significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons.  These results demonstrate ZCCHC17’s role in neuronal RNA processing and its interactions with pathology and cognitive resilience in AD.