SNX19 in human autopsy brains and cerebral organoids

Abstract

AbstractBackgroundThe gene encoding sorting nexin SNX19 is highly expressed in neurons. SNX19 modulates synaptic functions that have been implicated in Aβ formation and tau phosphorylation. In our recent postmortem brain transcriptomic study (n = 409), we found an association of SNX19 gene expression with increased schizophrenia risk. To date, this gene has not been studied in AD. In this project, we will define AD risk single nucleotide variants (SNVs) at this locus, linking the SNVs to SNX19 gene expression and DNA methylation sites in human postmortem brains. we will test the hypothesis that SNX19 induces neuronal dysfunction and Alzheimer’s disease (AD)‐related pathologies in hiPSCs derived cerebral organoids.MethodWe collected human postmortem bulk brain dorsolateral prefrontal cortex (DLPFC) RNA‐seq data from Religious Orders Study/Memory and Aging Project (ROSMAP N = 656). We obtained two human induced pluripotent stem cells (hiPSCs) from HipSci.ResultWe performed a multi‐trait analysis and identified single nucleotide variants (SNVs) in SNX19 that were associated with AD and DSST. To uncover the regulatory mechanism linked to the SNX19‐AD risk SNVs, we examined the possible association of these SNVs with SNX19 abundance. As expected, the SNVs are significantly associated with SNX19 gene expression in DLPFC from 656 aging brains generated by ROSMAP (p‐value < 1e‐20).Given the role of DNA methylation in influencing local gene expression and splicing in the human brain, we evaluated the association between SNV genotype and DNA methylation levels from 401 autopsy brains in our schizophrenia study. We identified cg14779329 as the top hit with schizophrenia functional SNV rs10791098. Interestingly, this CpG site was replicated to be associated with DSST‐risk SNVs in 692 ROSMAP brains.To determine whether SNX19 protein influences aspects of neurodegeneration, we have performed CRISPR gene editing in hiPSCs. We are generating cerebral organoids to assess the SNX19 impact on neuronal morphology, AD‐related pathologies and synaptic function.ConclusionOur study identified novel AD factors at SNX19 in human postmortem brains and will define its role in AD using human‐derived tissue cultures.