Abstract
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 Neu ronal Id entity ( NeuID )-a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimer's disease (AD) patients. Mechanistically, NeuID maintains neuronal identity by repressing developmental and glial genes via interaction with the PRC2 subunit EZH2 and regulation of H3K27me3. Knockdown of NeuID disrupts this repression, leading to impaired neuronal activity and memory formation. Importantly, CRISPRa-mediated NeuID overexpression restores neuronal function in Aβ42-treated neurons. These findings identify NeuID as a critical regulator of neuronal plasticity and position it as a promising therapeutic target for AD. ONE SENTENCE SUMMARY: We identify NeuID , 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.