Upregulated c-JUN induces aberrant transposable element mobilization, cGAS-STING activation and cell death in Alzheimer's disease

ABSTRACT: In this study we leveraged several lines of AD patient derived induced Pluripotent Stem Cells (iPSCs) and differentiated them into hippocampal neuronal progenitors, hippocampal CA3 neurons and cerebral organoids.  Our goals were to i) investigate the transcriptional networks altered in the AD lines at the different developmental stages (progenitors, neurons, organoids), ii) link the altered gene regulatory networks to aberrant AP-1 activity, and iii) to profile TEs aberrantly active in the AD lines, with the goal of identifying a mechanism for TE derepression and to unveil the consequences that this process has on neuronal physiology.  With these experiments, we demonstrate that many of the genes differentially expressed between the AD lines the healthy controls are c-JUN targets.  Further, we find that most of the aberrantly de-repressed TEs harbor the AP-1 binding motif, and that aberrant TE mobilization leads to cytoplasmic accumulation of RNA-DNA hybrids, observed both in the progenitors and in the organoids. Importantly this phenomenon elicits cGAS-STING activation and ultimately cell-death.  Notably, by using a c-JUN peptide that inhibits c-JUN phosphorylation, we demonstrate that c-JUN inhibition in the AD lines is sufficient to rescue the expression of many differentially expressed genes, and to significantly reduce aberrant TE mobilization, cytoplasmic RNA-DNA accumulation, cGAS-STING activation and cell death.  

ORGANISM(S): Homo sapiens

PROVIDER: GSE213610 | GEO | 2023/09/07

REPOSITORIES: GEO