NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

Pradhan, R.; Petrovic, Z.; Sakib, M. S.; Schroeder, S.; Krueger, D. M.; Pena, T.; Diniz, E.; Burkhardt, S.; Schuetz, A.-L.; Grz_dzielewska, I.; Toischer, K.; Stein, T. D.; Blusztajn, J. K.; Delalle, I.; Radulovic, J.; Sananbenesi, F.; Fischer, A.

doi:10.1101/2025.06.01.657217

bioRxiv · 10.1101/2025.06.01.657217

NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease

Pradhan, R.·Petrovic, Z.·Sakib, M. S.·Schroeder, S.·Krueger, D. M.·Pena, T.·Diniz, E.·Burkhardt, S.·Schuetz, A.-L.·Grz_dzielewska, I.·Toischer, K.·Stein, T. D.·Blusztajn, J. K.·Delalle, I.·Radulovic, J.·Sananbenesi, F.·Fischer, A.

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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 Neuronal Identity (NeuID)--a conserved, brain-enriched transcript expressed exclusively in neurons. NeuID is downregulated in the brains of Alzheimers 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 A{beta}42-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 summaryWe identify NeuID, a novel brain and neuron-specific long non-coding RNA downregulated in Alzheimers disease, as a key regulator of neuronal identity and a promising therapeutic target to restore neuronal function.

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Pradhan, R., Petrovic, Z., Sakib, M. S., Schroeder, S., Krueger, D. M., Pena, T., Diniz, E., Burkhardt, S., Schuetz, A.-L., Grz_dzielewska, I., Toischer, K., Stein, T. D., Blusztajn, J. K., Delalle, I., Radulovic, J., Sananbenesi, F., Fischer, A.. 2025-06-03. NeuID, a novel neuron-specific lncRNA, resolved a key epigenetic mechanisms linking gene silencing to Alzheimer's disease. https://doi.org/10.1101/2025.06.01.657217

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