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

Fahad Paryani, Ji-Sun Kwon, Christopher W. Ng, Kelly Jakubiak, Nacoya Madden, Kenneth Ofori, Alice Tang, Hong Lu, Shengnan Xia, Juncheng Li, Aayushi Mahajan, Shawn M. Davidson, Anna O. Basile, Caitlin McHugh, Jean Paul Vonsattel, Richard Hickman, Michael C. Zody, David E. Housman, James E. Goldman, Andrew S. Yoo, Vilas Menon () and Osama Al-Dalahmah ()
Additional contact information
Fahad Paryani: Columbia University Irving Medical Center
Ji-Sun Kwon: Department of Developmental Biology Washington University School of Medicine in St. Louis
Christopher W. Ng: Department of Biological Engineering
Kelly Jakubiak: Columbia University Irving Medical Center
Nacoya Madden: Columbia University Irving Medical Center
Kenneth Ofori: Columbia University Irving Medical Center
Alice Tang: Columbia University Irving Medical Center
Hong Lu: Columbia University Irving Medical Center
Shengnan Xia: Columbia University Irving Medical Center
Juncheng Li: Columbia University Irving Medical Center
Aayushi Mahajan: Columbia University Irving Medical Center
Shawn M. Davidson: Northwestern University
Anna O. Basile: New York Genome Center
Caitlin McHugh: New York Genome Center
Jean Paul Vonsattel: Columbia University Irving Medical Center
Richard Hickman: Columbia University Irving Medical Center
Michael C. Zody: New York Genome Center
David E. Housman: Department of Biological Engineering
James E. Goldman: Columbia University Irving Medical Center
Andrew S. Yoo: Department of Developmental Biology Washington University School of Medicine in St. Louis
Vilas Menon: Columbia University Irving Medical Center
Osama Al-Dalahmah: Columbia University Irving Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50626-0

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