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Cited by 264Genetic Neurodegenerative DiseasesSingle-cell and spatial transcriptomicsNeuroinflammation and Neurodegeneration Mechanisms

Single-nucleus RNA-seq identifies Huntington disease astrocyte states

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Al-Dalahmah, Osama, Sosunov, Alexander A., Shaik, A., Ofori, Kenneth, Liu, Yang, Vonsattel, Jean Paul, Adorjan, Istvan, Menon, Vilas +1 more·2020·Acta Neuropathologica Communications
DOI 10.1186/s40478-020-0880-6PMC PMC7029580

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Abstract

Huntington Disease (HD) is an inherited movement disorder caused by expanded CAG repeats in the Huntingtin gene. We have used single nucleus RNASeq (snRNASeq) to uncover cellular phenotypes that change in the disease, investigating single cell gene expression in cingulate cortex of patients with HD and comparing the gene expression to that of patients with no neurological disease. In this study, we focused on astrocytes, although we found significant gene expression differences in neurons, oligodendrocytes, and microglia as well. In particular, the gene expression profiles of astrocytes in HD showed multiple signatures, varying in phenotype from cells that had markedly upregulated metallothionein and heat shock genes, but had not completely lost the expression of genes associated with normal protoplasmic astrocytes, to astrocytes that had substantially upregulated glial fibrillary acidic protein ( GFAP ) and had lost expression of many normal protoplasmic astrocyte genes as well as metallothionein genes. When compared to astrocytes in control samples, astrocyte signatures in HD also showed downregulated expression of a number of genes, including several associated with protoplasmic astrocyte function and lipid synthesis. Thus, HD astrocytes appeared in variable transcriptional phenotypes, and could be divided into several different “states”, defined by patterns of gene expression. Ultimately, this study begins to fill the knowledge gap of single cell gene expression in HD and provide a more detailed understanding of the variation in changes in gene expression during astrocyte “reactions” to the disease.

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  • Single-cell and single-nucleus RNAseq studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD, AD, and MS that do not clearly comply with A1-A2 profiles.

    “For example, single-cell and single-nucleus RNAseq (scRNAseq and snRNAseq, respectively) studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD74, AD75,78, and MS40 that do not clearly comply with A1–A2 profiles.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [74]

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  • Instead of individual markers, signatures composed of a combination of markers with specified levels of expression or relative fold-changes are required to identify astrocyte phenotypes.

    “Thus, instead of individual markers, signatures composed of a combination of markers with specified levels of expression or relative fold-changes are required to identify astrocyte phenotypes74.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [74]

    The Methods section ('Supervised classification of astrocytes'; page unavailable) assigns astrocytes to states using specified expression thresholds for three genes, supporting the use of combined marker signatures. The paper does not establish the broader claim that such signatures are required, rather than individual markers, to identify astrocyte phenotypes generally. (LLM, conf=0.84)

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  • Only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD or AD, or from several mouse models of acute injuries and chronic diseases of the CNS.

    “Importantly, only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD74 or AD75,76, or from several mouse models of acute injuries and chronic diseases of the CNS42,69,76,77.”

    From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [74]

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Cited by

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Authors
Al-Dalahmah, O., Sosunov, A. A., Shaik, A., Ofori, K., Liu, Y., Vonsattel, J. P., Adorjan, I., Menon, V., & Goldman, J. E.
Affiliations
  • Columbia University (US)
  • Alfaisal University (SA)
Corresponding author
Goldman, James E.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2020-02-18
Volume
8
Issue
1
Pages
19-19
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-020-0880-6
PMC
PMC7029580
OpenAlex
W3007066794
Cited by
264
References
11
Citations by year
2026: 22 · 2025: 22 · 2024: 46 · 2023: 43 · 2022: 61 · 2021: 52 · 2020: 17 · 2012: 1
FWCI
19.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Columbia Academic Commons (Columbia University)
Funders
  • Hereditary Disease Foundation (19-1262)
  • Columbia University Taub Institute Innovation Award
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Huntington's disease, astrocytes, single-nucleus RNA sequencing, cingulate cortex, astrocyte phenotype, glial fibrillary acidic protein, metallothionein, heat shock genes, protoplasmic astrocyte, lipogenesis, oligodendrocytes, microglia, neuronal gene expression, CAG repeat expansion
MeSH terms
Adult, Aged, Astrocytes, Female, Gyrus Cinguli, Humans, Huntington Disease, Male, Middle Aged, Gene Expression, Sequence Analysis, RNA, Single-Cell Analysis

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