NeuID is a novel neuron-specific lncRNA that regulates neuronal function in Alzheimer’s disease

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 FANS with total RNA-sequencing and single-nuclei RNA sequencing approaches using human and mouse brain tissue to identify novel lncRNAs specific to neurons, and potentially associated with neurodegenerative diseases. We discovered a novel brain-specific lncRNA, the we named 'NeuID', that is specifically expressed in neuronal cells in the 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. Additionally, NeuID KD led to decreased dendritic spine density and reduced neuronal network activity in MEA recordings. Furthermore, we demonstrate that NeuID interacts with EZH2, a component of the PRC2 complex, and mediates the h3k27me3 levels of Olig2 transcription factor. Notably, CRISPRa mediated overexpression of NeuID resulted in the rescue of functional impairment caused by AD-related pathological Aβ oligomers. Overall, our findings identify a novel brain and neuron-exclusive lncRNA that regulates neuronal function, is dysregulated in AD, and might be a potential therapeutic target against neuronal pathology in AD.