Abstract ZCCHC17 is a putative master regulator of synaptic gene dysfunction in Alzheimer’s Disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis. 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 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 interaction with pathology and cognitive resilience in AD, and suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. Significance Abnormal RNA processing is an important component of AD pathophysiology. We show here that ZCCHC17, a previously identified putative master regulator of synaptic dysfunction in AD, plays a role in neuronal RNA processing, and illustrate that ZCCHC17 dysfunction is sufficient to explain some of the splicing abnormalities seen in AD brain tissue, including synaptic gene splicing abnormalities. Using data from human patients, we demonstrate that ZCCHC17 mRNA levels correlate with cognitive resilience in the setting of AD pathology. These results suggest that maintenance of ZCCHC17 function may be a therapeutic strategy for supporting cognitive function in AD patients, and motivate future work examining a possible role of abnormal RNA processing in AD-related cognitive decline.

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