TY  - JOUR
AU  - Schröder, Sophie
AU  - Fuchs, Ulrike
AU  - Gisa, Verena
AU  - Pena, Tonatiuh
AU  - Krüger, Dennis M
AU  - Hempel, Nina
AU  - Burkhardt, Susanne
AU  - Salinas, Gabriela
AU  - Schütz, Anna-Lena
AU  - Delalle, Ivana
AU  - Sananbenesi, Farahnaz
AU  - Fischer, Andre
TI  - PRDM16-DT is a novel lncRNA that regulates astrocyte function in Alzheimer's disease.
JO  - Acta neuropathologica
VL  - 148
IS  - 1
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2024-01091
SP  - 32
PY  - 2024
AB  - 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.
KW  - Astrocytes: metabolism
KW  - Astrocytes: pathology
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - RNA, Long Noncoding: genetics
KW  - RNA, Long Noncoding: metabolism
KW  - Animals
KW  - Humans
KW  - Mice
KW  - DNA-Binding Proteins: genetics
KW  - DNA-Binding Proteins: metabolism
KW  - Transcription Factors: genetics
KW  - Transcription Factors: metabolism
KW  - Male
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Neurons: metabolism
KW  - Neurons: pathology
KW  - Mice, Inbred C57BL
KW  - Alzheimer’s disease (Other)
KW  - Astrocyte (Other)
KW  - Brain (Other)
KW  - Long-non-coding RNA (Other)
KW  - Postmortem human brain (Other)
KW  - RNA, Long Noncoding (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
KW  - PRDM16 protein, human (NLM Chemicals)
KW  - Prdm16 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11362476
C6  - pmid:39207536
DO  - DOI:10.1007/s00401-024-02787-x
UR  - https://pub.dzne.de/record/271879
ER  -