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Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

Lee, Hyeseung and Fenster, Robert J. and Pineda, S. Sebastian and Gibbs, Whitney S. and Mohammadi, Shahin and Davila-Velderrain, Jose and Garcia, Francisco J. and Therrien, Martine and Novis, Hailey S. and Gao, Fan and Wilkinson, Hilary and Vogt, Thomas and Kellis, Manolis and LaVoie, Matthew J. and Heiman, Myriam (2020) Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation. Neuron, 107 (5). pp. 891-908. ISSN 0896-6273. https://resolver.caltech.edu/CaltechAUTHORS:20200717-105615475

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Abstract

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.neuron.2020.06.021DOIArticle
ORCID:
AuthorORCID
Fenster, Robert J.0000-0001-6299-9612
Pineda, S. Sebastian0000-0002-8903-0550
Mohammadi, Shahin0000-0001-8734-2326
Davila-Velderrain, Jose0000-0003-0271-6267
Wilkinson, Hilary0000-0002-0401-9329
Kellis, Manolis0000-0001-7113-9630
LaVoie, Matthew J.0000-0002-2583-1578
Additional Information:© 2020 Elsevier Inc. Received: December 2, 2019; Revised: April 7, 2020; Accepted: June 22, 2020; Published: July 17, 2020. This study was supported by funding from the CHDI Foundation, NIH/NINDS (1 R01 NS100802), and the Broderick fund for Phytocannabinoid Research at MIT to M.H. and the JPB Foundation to M.H. and H.L.; NIH (R25MH101076) to R.J.F.; NIH (5T32EB019940-05) to S.S.P.; NIH NIA NIMH NINDS NHGRI (R01AG062335, R01AG058002, RF1AG054012, RF1AG062377, R01MH109978, U01MH119509, U01NS110453, andR01HG008155) to M.K.; and NIH/NINDS (NS065013) to M.J.L. RNA sequencing was performed at the MIT BioMicro Center, the UCSF Functional Genomics Core, and the Broad Institute Genomics Platform. The authors thank Dr. Duanduan Ma for assistance with the ChIP-seq analysis, Dr. Kyriakitsa Galani and Julio Mantero for preparing the snRNA-seq libraries, Dr. Li-Lun Ho for assistance with sequencing the libraries, Dr. Hanseruedi Mathys for assistance with the nuclei isolation protocol, Alex Powers for assistance with mouse stereotaxic surgery, Ruth Kulicke for assistance with mouse handling and tissue dissection, and Brenda Lager for assistance with the coordination of mouse breeding and shipments. The authors additionally thank the NIH NeuroBioBank and the University of Alabama at Birmingham for providing the human HD and control case samples used in this study. Author Contributions: M.H. designed the study with help from H.L., R.J.F., H.W., T.V., and M.J.L. M.H. and R.J.F. performed all of the TRAP purifications. F.G. conducted the Retro-TRAP data analysis. H.L. conducted TRAP data filtering and analysis and performed all innate immune signaling mouse studies. S.S.P., S.M., J.D.-V., F.J.G., H.L., and M.K. performed the snRNA-seq studies. M.T. assisted in TRAP sample harvest and TRAP data filtering and analysis. H.S.N. performed the OXPHOS complex assays, and W.S.G. performed the in vitro human neuron studies. M.H. supervised the project and wrote the manuscript with comments from all authors. Declaration of Interests: M.H. is a member of the Hereditary Disease Foundation’s Scientific Advisory Board, and T.V. and H.W. are employed by CHDI Management, Inc., as advisors to the CHDI Foundation, Inc.
Funders:
Funding AgencyGrant Number
CHDI FoundationUNSPECIFIED
NIH1 R01 NS100802
Massachusetts Institute of Technology (MIT)UNSPECIFIED
JPB FoundationUNSPECIFIED
NIHR25MH101076
NIH Predoctoral Fellowship5T32EB019940-05
NIHR01AG062335
NIHR01AG058002
NIHRF1AG054012
NIHRF1AG062377
NIHR01MH109978
NIHU01MH119509
NIHU01NS110453
NIHR01HG008155
NIHNS065013
Issue or Number:5
Record Number:CaltechAUTHORS:20200717-105615475
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200717-105615475
Official Citation:Hyeseung Lee, Robert J. Fenster, S. Sebastian Pineda, Whitney S. Gibbs, Shahin Mohammadi, Jose Davila-Velderrain, Francisco J. Garcia, Martine Therrien, Hailey S. Novis, Fan Gao, Hilary Wilkinson, Thomas Vogt, Manolis Kellis, Matthew J. LaVoie, Myriam Heiman, Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation, Neuron, Volume 107, Issue 5, 2020, Pages 891-908.e8, ISSN 0896-6273, https://doi.org/10.1016/j.neuron.2020.06.021. (http://www.sciencedirect.com/science/article/pii/S089662732030475X)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104429
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Jul 2020 18:22
Last Modified:18 Sep 2020 17:53

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