Journal Article

DZNE-2026-00385

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png lncRNA Glelr modulates microglia inflammatory programs in association with PU.1.

Pradhan, R. (First author)DZNE* ; Sakib, M. S.DZNE* ; Kaurani, L.DZNE* ; Krüger, D. M.DZNE* ; Pena, T.DZNE* ; Burkhardt, S.DZNE* ; Schütz, A.-L.DZNE* ; Kronenberg-Versteeg, D.DZNE* ; Delalle, I. ; Sananbenesi, F.DZNE* ; Fischer, A. (Last author)DZNE*

2026
Elsevier [Amsterdam]

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Please use a persistent id in citations: doi:10.1016/j.nbd.2026.107366

Abstract: Long non-coding RNAs (lncRNAs) are emerging as key regulators of brain function, but their contribution to microglial aging and neurodegenerative disease remains largely unknown. Because only 1.5% of the human genome encodes proteins, whereas the vast majority of transcripts belong to the largely unexplored non-coding RNAome, elucidating the functions of non-coding RNAs provides an unprecedented opportunity to expand the space for therapeutic discovery. We recently identified the glia-enriched lncRNA Glelr as upregulated in the aging mouse hippocampus. Here, we investigated its function in microglia and its human homolog GLELR. We found that Glelr/GLELR is expressed in both astrocytes and microglia and increases with age. Knockdown of Glelr in primary microglia led to enhanced expression of pro-inflammatory cytokines, including TNFα, and increased phagocytic activity. RNA-sequencing revealed widespread transcriptional changes enriched for TNF and complement signaling pathways. The human homolog GLELR showed conserved functions in iPSC-derived microglia, where its loss similarly promoted inflammatory gene expression and phagocytosis. Mechanistically, Glelr interacts with the microglial transcription factor PU.1, and its depletion overlapped with PU.1-driven transcriptional programs. Consistent with these findings, GLELR expression was significantly reduced in postmortem Alzheimer's disease (AD) brains, and AD-associated genes were enriched among Glelr-regulated targets. Together, our results identify Glelr/GLELR as a conserved, aging-associated lncRNA that modulates microglial inflammatory states through interaction with PU.1. This work links glial lncRNA regulation to AD-related neuroinflammation and suggests GLELR as a potential molecular target to fine-tune microglial activity in neurodegenerative diseases.

Keyword(s): RNA, Long Noncoding: metabolism (MeSH) ; RNA, Long Noncoding: genetics (MeSH) ; Microglia: metabolism (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Trans-Activators: metabolism (MeSH) ; Trans-Activators: genetics (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Proto-Oncogene Proteins: genetics (MeSH) ; Inflammation: metabolism (MeSH) ; Inflammation: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Cells, Cultured (MeSH) ; Aging: metabolism (MeSH) ; Astrocytes: metabolism (MeSH) ; 3222401L13Rik/ENSG00000272070 ; Alzheimer's disease ; Long non-coding RNA (lncRNA) ; Microglia ; Neuroinflammation ; Non-coding RNAome ; PU.1 (SPI1) ; RNA, Long Noncoding ; Trans-Activators ; Proto-Oncogene Proteins

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Bioinformatics and Genome Dynamics Core (Göttingen) (Bioinformatics Unit (Göttingen))
3. Genome Dynamics in Neurodegenerative Diseases (AG Sananbenesi)
4. Glial Cell Biology (AG Kronenberg-Versteeg)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 899 - ohne Topic (POF4-899) (POF4-899)

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