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

• DOI: 10.1038/s41467-024-50626-0
• Publication Date: 2024-08-08T01:02:01Z
• Authors: 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; Osama Al-Dalahmah
• Keywords: Neurons; Male; 570; Huntingtin Protein; 0303 health sciences; Science; Q; ICTS (Institute of Clinical and Translational Sciences); 610; Brain; Middle Aged; Lipid Metabolism; Multiomics; Article; 03 medical and health sciences; Huntington Disease; Astrocytes; Lipidomics; Medicine and Health Sciences; Humans; Female; Metallothionein; Aged

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.