LncRNA Gas5, a Target of the Nonsense-Mediated Decay Pathway in the Brain, Regulates Neuroinflammation and Neurodegenerative Disease Pathways in a Tauopathy Mouse Model.

Overview

1. Research Service, James A. Haley Veterans’ Hospital, Tampa, FL 33612, USA; (M.K.-H.); (B.W.); (R.S.P.); (L.J.B.)
2. Byrd Alzheimer’s Center and Research Institute, Tampa, FL 33613, USA; (L.V.); (A.H.); (A.D.)
3. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
4. Department of Chemistry, University of South Florida, Tampa, FL 33612, USA

Abstract

Dysregulation of target genes of nonsense-mediated decay (NMD) in the brain remains sparsely known in tauopathies. PS19 transgenic mice expressing human mutant P301S tau were evaluated for levels of lncRNA Gas5, a target of NMD. The results show Gas5 decreased in the brains of PS19 mice as they aged. We evaluated the consequences of blocking the NMD-mediated turnover of Gas5 using a small molecule administered intranasally to PS19 mice. The results show NPC86 disassociated Upf1 and Gas5, thereby hindering NMD. NPC86 treatment increased Gas5 levels in the cortex of male PS19 mice concurrent with a highly significant decrease in pTau S214 and neuroinflammatory genes while increasing insulin signaling. Consequently, digital spatial profiling identified Gas5-regulated genes and pathways. NPC86 treatment enhanced neuronal homeostasis, synaptic vesicle transport and mitochondrial function and downregulated neuroinflammatory pathways. The nodal genes in Parkinson’s signaling pathway, the multiple sclerosis signaling pathway, the Gα(s) signaling pathway, the neuroinflammation signaling pathway, and the interferon gamma signaling pathway were decreased in response to NPC86. The study demonstrates the potential of selectively stabilizing NMD-target lncRNA Gas5 levels to alleviate early neurodegenerative pathology in tauopathy.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• zenodo:22230810 — at Zenodo; found in “Data Availability Statement”

Data Availability Statement

All data are available in the main text or the Supplementary Materials. DSP data are uploaded to Zenodo https://zenodo.org/records/22230810 (accessed on 10 June 2026).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 6 keywords, 14 MeSH terms, 4 funders, 51 references.

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This paper

Krause-Hauch, M., Wang, B., Patel, R. S., Verdina, L., Hedrick, A., Blair, L. J., Dharap, A., Cai, J., & Patel, N. A. (2026). LncRNA Gas5, a Target of the Nonsense-Mediated Decay Pathway in the Brain, Regulates Neuroinflammation and Neurodegenerative Disease Pathways in a Tauopathy Mouse Model. International journal of molecular sciences, 27(17), 7675. https://doi.org/10.3390/ijms27177675

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