PRDM16-DT: A Brain and Astrocyte-Specific lncRNA Implicated in Alzheimer’s Disease

Abstract

AbstractAstrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer’s disease (AD), highlighting the growing interest in targeting astrocyte function to address early phases of AD pathogenesis. While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNAPRDM16-DTas highly enriched in the human brain, where it is almost exclusively expressed in astrocytes.PRDM16-DTand its murine homolog,Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown ofPRDM16-DTandPrdm16osrevealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression ofPrdm16osmitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance ofPRDM16-DTin astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction