학술논문
ZCCHC17 Modulates Neuronal RNA Splicing and Supports Cognitive Resilience in Alzheimer's Disease.
Document Type
Article
Author
Bartosch, Anne Marie W.; Youth, Elliot H. H.; Hansen, Shania; Yiyang Wu; Buchanan, Heather M.; Kaufman, Maria E.; Xiao, Harrison; So Yeon Koo; Ashok, Archana; Sivakumar, Sharanya; Soni, Rajesh K.; Dumitrescu, Logan C.; Lam, Tiffany G.; Ropri, Ali S.; Lee, Annie J.; Klein, Hans-Ulrich; Vardarajan, Badri N.; Bennett, David A.; Young-Pearse, Tracy L.; De Jager, Philip L.
Source
Subject
Language
ISSN
0270-6474
Abstract
ZCCHC17 is a putativemaster 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 using data fromhuman autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) 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, amajority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a 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 the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. [ABSTRACT FROM AUTHOR]