Journal Article

DZNE-2024-01091

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PRDM16-DT is a novel lncRNA that regulates astrocyte function in Alzheimer's disease.

Schröder, S.DZNE* ; Fuchs, U.DZNE* ; Gisa, V.DZNE* ; Pena, T.DZNE* ; Krüger, D. M.DZNE* ; Hempel, N.DZNE* ; Burkhardt, S.DZNE* ; Salinas, G. ; Schütz, A.-L.DZNE* ; Delalle, I. ; Sananbenesi, F.DZNE* ; Fischer, A. (Last author)DZNE*

2024
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-024-02787-x

Abstract: Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer's disease (AD). While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction.

Keyword(s): Astrocytes: metabolism (MeSH) ; Astrocytes: pathology (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; RNA, Long Noncoding: genetics (MeSH) ; RNA, Long Noncoding: metabolism (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Transcription Factors: genetics (MeSH) ; Transcription Factors: metabolism (MeSH) ; Male (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Alzheimer’s disease ; Astrocyte ; Brain ; Long-non-coding RNA ; Postmortem human brain ; RNA, Long Noncoding ; DNA-Binding Proteins ; Transcription Factors ; PRDM16 protein, human ; Prdm16 protein, mouse

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Genome Dynamics in Neurodegenerative Diseases (AG Sananbenesi)
3. Bioinformatics and Genome Dynamics Core (Göttingen) (Bioinformatics Unit (Göttingen))

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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