Multi-omic analysis of Huntington’s disease reveals a compensatory astrocyte state
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.
Authors
- Richard A. Hickman (ORCID: https://orcid.org/0000-0002-8329-6083)
- Shawn M. Davidson (ORCID: https://orcid.org/0000-0002-3475-0382)
- Kenneth Ofori (ORCID: https://orcid.org/0000-0002-4422-2882)
- James E. Goldman (ORCID: https://orcid.org/0000-0003-2135-8936)
- Anna O. Basile (ORCID: https://orcid.org/0000-0001-5112-5880)
- Vilas Menon (ORCID: https://orcid.org/0000-0002-4096-8601)
- Fahad Paryani (ORCID: https://orcid.org/0000-0003-1418-1386)
- Michael C. Zody (ORCID: https://orcid.org/0000-0001-6594-7199)
- Christopher Ng (ORCID: https://orcid.org/0000-0001-8815-7958)
- Alice Tang (ORCID: https://orcid.org/0000-0002-3263-5030)
- Aayushi Mahajan (ORCID: https://orcid.org/0000-0003-3966-2936)
- Hong Lü (ORCID: https://orcid.org/0000-0003-4389-7252)
- Osama Al‐Dalahmah (ORCID: https://orcid.org/0000-0002-3442-5459)
- Nacoya Madden
- Ji‐Sun Kwon
- Andrew S.J. Yoo (ORCID: https://orcid.org/0000-0002-0304-3247)
- Kelly Jakubiak (ORCID: https://orcid.org/0009-0002-6932-4460)
- Juncheng Li (ORCID: https://orcid.org/0009-0008-0934-1027)
- Caitlin P. McHugh (ORCID: https://orcid.org/0000-0001-8913-2058)
- Shengnan Xia (ORCID: https://orcid.org/0009-0001-3728-6669)
- David E. Housman
- Jean Paul Vonsattel
Institutions
- Northwestern University (US)
- Washington University in St. Louis (US)
- Columbia University Irving Medical Center (US)
- MIND Research Institute (US)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Institute on Aging (US)
- New York Genome Center (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-08
- DOI
- https://doi.org/10.1038/s41467-024-50626-0
- Citations
- 27
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 7.24
Funders
- American Brain Tumor Association
- National Institutes of Health
- National Institute on Aging