2. Academic Validation
  3. Multi-omic analysis of Huntington's disease reveals a compensatory astrocyte state

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

  • Nat Commun. 2024 Aug 8;15(1):6742. doi: 10.1038/s41467-024-50626-0.
Fahad Paryani 1,  Ji-Sun Kwon 2,  Christopher W Ng 3,  Kelly Jakubiak 4,  Nacoya Madden 4,  Kenneth Ofori 4,  Alice Tang 4,  Hong Lu 4,  Shengnan Xia 4,  Juncheng Li 4,  Aayushi Mahajan 4,  Shawn M Davidson 5,  Anna O Basile 6,  Caitlin McHugh 6,  Jean Paul Vonsattel 4,  Richard Hickman 4,  Michael C Zody 6,  David E Housman 3,  James E Goldman 4 7,  Andrew S Yoo 2,  Vilas Menon 8 9,  Osama Al-Dalahmah 10 11
Affiliations

Affiliations

  • 1 Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • 2 Department of Developmental Biology Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
  • 3 Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA, USA.
  • 4 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
  • 5 Northwestern Feinberg School of Medicine, Northwestern University, Evanston, IL, USA.
  • 6 New York Genome Center, New York, NY, USA.
  • 7 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
  • 8 Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA. vm2545@cumc.columbia.edu.
  • 9 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. vm2545@cumc.columbia.edu.
  • 10 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. oa2298@cumc.columbia.edu.
  • 11 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. oa2298@cumc.columbia.edu.
PMID: 39112488 DOI: 10.1038/s41467-024-50626-0
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.

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