LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3

Sophie Schröder; M Sadman Sakib; Dennis M Krüger; Tonatiuh Pena; Susanne Burkhardt; Anna-Lena Schütz; Farahnaz Sananbenesi; André Fischer

doi:10.3390/ncrna11010002

LncRNA 3222401L13Rik Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3

Noncoding RNA. 2025 Jan 9;11(1):2. doi: 10.3390/ncrna11010002.

Authors

Sophie Schröder¹, M Sadman Sakib¹, Dennis M Krüger^{1

2

3}, Tonatiuh Pena^{1

2}, Susanne Burkhardt^{1

3}, Anna-Lena Schütz³, Farahnaz Sananbenesi³, André Fischer^{1

4

5}

Affiliations

¹ Department for Systems Medicine and Epigenetics, German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany.
² Bioinformatics Unit, German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany.
³ Research Group for Genome Dynamics in Brain Diseases, German Center for Neurodegenerative Diseases, 37075 Göttingen, Germany.
⁴ Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany.
⁵ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany.

Abstract

Aging leads to cognitive decline and increased risk of neurodegenerative diseases. While molecular changes in central nervous system (CNS) cells contribute to this decline, the mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) are key regulators of cellular functions. Background/Objectives: The roles of lncRNAs in aging, especially in glial cells, are not well characterized. Methods: We investigated lncRNA expression in non-neuronal cells from aged mice and identified 3222401L13Rik, a previously unstudied lncRNA, as upregulated in astrocytes during aging. Results: Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes for neuronal support and synapse organization, a function conserved in human iPSC-derived astrocytes. A 3222401L13Rik interacts with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and overexpression of Npas3 rescues deficits in astrocytes lacking 3222401L13Rik. Conclusions: These data suggest that 3222401L13Rik upregulation may help delay age-related cognitive decline.

Keywords: Alzheimer’s disease; aging; astrocytes; brain; lncRNA; neurodegenerative diseases; non-coding RNA; transcriptomics.

Grants and funding

A.F. was supported by the DFG (Deutsche Forschungsgemeinschaft) priority program 1738, SFB1286 and GRK2824; The German Federal Ministry of Science and Education (BMBF) via the ERA-NET Neuron project EPINEURODEVO; The EU Joint Programme- Neurodegenerative Diseases (JPND)—EPI-3E; Germany’s Excellence Strategy—EXC 2067/1 390729940. F.S. was supported by the GoBIO project miRassay (16LW0055) by the German Federal Ministry of Science and Education.