NeuID, a novel neuron-specific lncRNA, resolves a key epigenetic mechanism linking gene silencing to Alzheimer's disease.

Unlabelled: The increasing evidence that non-coding RNAs can become deregulated during pathogenesis is dramatically expanding the space for drug discovery beyond the protein-coding genome. Long noncoding RNAs (lncRNAs) are emerging as key regulators of cellular function, yet most remain uncharacterized. Here, we identify a previously unstudied lncRNA, which we named ronal entity ( )-a conserved, brain-enriched transcript expressed exclusively in neurons. is downregulated in the brains of Alzheimer's disease (AD) patients. Mechanistically, maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated overexpression restores neuronal function in Aβ42-treated neurons. These findings identify as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD.

One Sentence Summary: We identify , a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimer's disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.