NeuID: A novel lncRNA exclusively expressed in the brain and controls neuronal function and identity

Non-coding RNAs are transcripts that do not encode proteins and comprise 98.5% of the human transcriptome. Among these, long non-coding RNAs (lncRNAs) have been implicated in various biological functions, including the control of gene expression and translation. The central nervous system (CNS) harbors a diverse array of lncRNA transcripts, yet the functions of many remain largely unexplored. In this study, we employed bulk and single-cell RNA sequencing approaches using human and mouse brain tissue to identify novel lncRNAs in both neuronal and non-neuronal cells, potentially associated with neurodegenerative diseases. We discovered a novel brain-specific lncRNA, termed 'NeuID', specifically expressed in neurons of both mouse and human brains. NeuID expression was found to be reduced in the brains of Alzheimer’s disease (AD) patients. Knockdown (KD) of NeuID resulted in the downregulation of synaptic plasticity genes and the upregulation of genes associated with glial cell development. Additionally, NeuID KD led to decreased dendritic spine density and reduced neuronal network activity. Furthermore, we demonstrated that NeuID interacts with EZH2, a component of the PRC2 complex known to play essential roles in cell fate determination. Overall, our findings identify a unique brain and neuron-exclusive lncRNA that regulates neuronal function, is dysregulated in AD, and plays a role in maintaining neuronal identity.