Multi-omic analysis of Huntington's disease reveals a compensatory astrocyte state.

Autor: Paryani F; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA., Kwon JS; Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Ng CW; Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA., Jakubiak K; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Madden N; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Ofori K; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Tang A; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Lu H; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Xia S; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Li J; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Mahajan A; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Davidson SM; Northwestern Feinberg School of Medicine, Northwestern University, Evanston, IL, USA., Basile AO; New York Genome Center, New York, NY, USA., McHugh C; New York Genome Center, New York, NY, USA., Vonsattel JP; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Hickman R; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA., Zody MC; New York Genome Center, New York, NY, USA., Housman DE; Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA., Goldman JE; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA., Yoo AS; Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, USA., Menon V; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA. vm2545@cumc.columbia.edu.; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. vm2545@cumc.columbia.edu., Al-Dalahmah O; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. oa2298@cumc.columbia.edu.; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. oa2298@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 08; Vol. 15 (1), pp. 6742. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1038/s41467-024-50626-0
Abstrakt: The mechanisms underlying the selective regional vulnerability to neurodegeneration in Huntington's disease (HD) have not been fully defined. To explore the role of astrocytes in this phenomenon, we used single-nucleus and bulk RNAseq, lipidomics, HTT gene CAG repeat-length measurements, and multiplexed immunofluorescence on HD and control post-mortem brains. We identified genes that correlated with CAG repeat length, which were enriched in astrocyte genes, and lipidomic signatures that implicated poly-unsaturated fatty acids in sensitizing neurons to cell death. Because astrocytes play essential roles in lipid metabolism, we explored the heterogeneity of astrocytic states in both protoplasmic and fibrous-like (CD44+) astrocytes. Significantly, one protoplasmic astrocyte state showed high levels of metallothioneins and was correlated with the selective vulnerability of distinct striatal neuronal populations. When modeled in vitro, this state improved the viability of HD-patient-derived spiny projection neurons. Our findings uncover key roles of astrocytic states in protecting against neurodegeneration in HD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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