Mislocalization of mitochondrial DNA and subcellular RNA is a convergent mechanism in neurodegenerative dementias and is rescued by VCP ATPase inhibition

Nucleocytoplasmic transport defects have been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). However, there have been few systematic efforts to evaluate transcriptome-wide subcellular mRNA distribution in these conditions, which if deregulated may significantly compromise cellular homeostasis. Here, we assessed mRNA nucleocytoplasmic localization by performing transcriptome-wide profiling on nuclear and cytoplasmic fractions of human iPSC-derived cortical neurons from healthy individuals compared to those from both familial AD and FTD patients. Our findings revealed that AD and FTD mutations induce significant changes in mRNA nucleocytoplasmic distribution. We additionally reveal the redistribution of mitochondrial-related transcripts across different mutations. The significant ‘leakage’ of mitochondrial RNA (mtRNA) into the cytosol in AD and FTD mutant neurons motivated us to examine the leakage of mtDNA. Importantly, we found abnormal cytoplasmic accumulation of mtDNA in AD and FTD cortical neurons, which is reversible with treatment using a pharmacological inhibitor of the VCP D2 ATPase domain.