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Single-Nucleus RNA-Seq Identifies Huntington Disease Astrocyte States Osama Al-Dalahmah1, Alexander A

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Single-Nucleus RNA-Seq Identifies Huntington Disease Astrocyte States Osama Al-Dalahmah1, Alexander A Al-Dalahmah et al. Acta Neuropathologica Communications (2020) 8:19 https://doi.org/10.1186/s40478-020-0880-6 RESEARCH Open Access Single-nucleus RNA-seq identifies Huntington disease astrocyte states Osama Al-Dalahmah1, Alexander A. Sosunov2, A. Shaik3, Kenneth Ofori1, Yang Liu1, Jean Paul Vonsattel1, Istvan Adorjan4, Vilas Menon5 and James E. Goldman1* 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. Keywords: Huntington disease, Astrocytes, Gene expression, Cingulate cortex, Single-cell RNA-sequencing Introduction Understanding the differences in microenvironment be- Huntington Disease (HD), a neurodegenerative disorder tween affected and relatively resistant regions may illu- caused by CAG repeats in the Huntingtin gene, leads to minate the cellular and molecular mechanisms underlying the accumulation of the mutant protein and an associated vulnerability and resilience to neurodegeneration. Astro- neuronal degeneration and gliosis [34]. Although Hun- cytes, in particular, are a key to maintaining the neuronal tingtin is expressed in all cell types, the neuropathology of microenvironment, and display regional variation across the disease shows substantial variation. For instance, there the dorsal-ventral, rostral-caudal, and medial-lateral axes are caudal-rostral and medial-lateral gradients of severity according to developmentally-determined domains [55]. in the neostriatum [57], and relative sparing of the nucleus Additionally, astrocytes exhibit intra-regional heterogen- accumbens in advanced grade HD [44]. Neuronal degen- eity. For example, subpial and white matter astrocytes eration in the isocortex involves the motor and sensory contain more glial fibrillary acidic protein (GFAP) and cortices but relatively spares the superior parietal lobule CD44 than protoplasmic astrocytes but lower levels of [37], and in some patients, the anterior cingulate cortex is protoplasmic astrocyte markers, such as glutamate trans- also involved, and cortical layers III, V, and VI are espe- porters and glutamine synthetase [51]. Astrocytes in the cially vulnerable [45]. affected regions of the HD brain show a “reactive” state, generally defined by histochemistry or by an increase in * Correspondence: [email protected] GFAP [48, 58], but also by a decrease in the expression 1Department of Pathology & Cell Biology, Columbia University, New York and protein levels of the major astrocytic glutamate trans- City, NY, USA porter, EAAT2 [2, 9]. In mouse models of HD, expression Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Al-Dalahmah et al. Acta Neuropathologica Communications (2020) 8:19 Page 2 of 21 of mutant Huntingtin (mHTT) in astrocytes leads to de- with protoplasmic astrocytes, to astrocytes that had sub- crease in the expression of the glutamate transporter [5], stantially upregulated GFAP and had lost expression of and the failure to buffer extracellular potassium and glu- many normal protoplasmic genes as well as the MT genes. tamate leads to neuronal hyper-excitability and a HD-like The variation in astrocytes is not surprising, given that phenotype, which is reversed by restoration of astrocytic HD is a degenerative disease that progresses over years membrane conductance [53]. In addition, astrocytes in and one would not expect all astrocytes to respond syn- HD contribute to an inflammatory environment [16, 27], chronously during the course of the disease. which likely participates in the progression of the path- Studies like this one will begin to fill the knowledge ology. Thus, there is substantial evidence that astrocytes gap of single cell gene expression in HD and give us a play a primary role in the evolution of HD. more detailed understanding of the variation in changes Whereas bulk transcriptome-wide studies have pro- in gene expression during astrocyte “reactions.” Further- vided important insights into molecular changes in HD more, network building from these gene sets will help [1, 14, 15, 23, 29, 38], bulk samples comprise a mixture define interacting genes and important regulatory genes of cell types, so astrocyte-specific signatures in HD may behind reactive astrocyte states. be obscured. Single cell RNA sequencing (scRNAseq) is a powerful technique to interrogate cellular heterogen- Methods eity [6, 42]. Although brain banks house hundreds of Dissection of the cingulate cortex from frozen tissue frozen postmortem brain specimens, technical difficul- Postmortem anterior cingulate cortex specimens frozen ties limit the application of scRNAseq to these samples. during autopsy from control and grade III/IV HD were However, this is not a limitation of single nucleus RNA obtained from the New York Brain Bank. Four cases sequencing (snRNASeq), which accurately elucidates cel- (two HD and 2 control) were selected for snRNAseq and lular heterogeneity in a manner comparable to whole/ 12 cases (6 and 6) for bulk RNAseq, all with RNA integ- cytoplasmic scRNAseq [25], and can be applied to frozen rity numbers of > 7. Cortical wedges measuring ~ 5 × brain tissue [22]. This technique has been used to iden- 4 × 3 mm were dissected on a dry ice cooled stage and tify multiple novel, regionally-diversified cortical excita- processed immediately as described below. A table of tory and inhibitory neuronal sub-types [24]. Recently, the cases and controls used is provided in Table 1. massively parallel snRNASeq using droplet technology revealed cellular heterogeneity in the human postmor- Single nucleus RNAseq tem cortex and hippocampus [11, 17]. The disease- Nuclei were isolated as described in [22]. Briefly, cortical specific cell-type specific transcriptional signatures were tissue was homogenized in a Dounce homogenizer with described in oligodendroglia in multiple sclerosis [18] 10–15 strokes of the loose pestle and 10–15 strokes of and multiple cell types in Alzheimer Disease [31] and the tight pestle on ice in a Triton X-100 based, sucrose microglia in Alzheimer disease [39]. containing buffer. The suspension from each sample was In this study, we performed snRNASeq of fresh frozen filtered through a BD Falcon tubes with a cell strainer cingulate cortex from Grade III/IV HD patients and caps (Becton Dickinson, cat. no. 352235), washed, re- compared the results to those from non-neurological filtered, washed, followed by a cleanup step using iodixa- control patients to examine single cell differences in nol gradient centrifugation. The nuclear pellet was then gene expression. We have focused here on astrocytes, al- re-suspended in 1% BSA in nuclease-free PBS (contain- though we found significant differences in all cell types. ing RNAse inhibitors) and titrated to 1000 nuclei/μl. We examined the cingulate cortex, which is often af- The nuclear suspensions were processed by the Chro- fected in HD patients, because the cortical pathology is mium Controller (10x Genomics) using single Cell 3′ less severe than the neostriatal pathology, and because Reagent Kit v2 (Chromium Single Cell 3′ Library & Gel there is little known about cortical astrocyte pathology Bead Kit v2, catalog number: 120237; Chromium Single in HD. Finally, we focused on Grade III/IV to identify Cell A Chip Kit, 48 runs, catalog number: 120236; 10x astrocyte gene expression changes in an intermediate Genomics). stage of evolution rather than at an end stage. Overall, we found substantial
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