title: RNA-Seq of Huntington's disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation.
abstract: Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus. In contrast with previous studies that have required stimulation to elicit phenotypic abnormalities, we demonstrate significant transcriptional differences in HD monocytes in their basal, unstimulated state. This includes previously undetected increased resting expression of genes encoding numerous proinflammatory cytokines, such as IL6 Further pathway analysis revealed widespread resting enrichment of proinflammatory functional gene sets, while upstream regulator analysis coupled with Western blotting suggests that abnormal basal activation of the NFĸB pathway plays a key role in mediating these transcriptional changes. That HD myeloid cells have a proinflammatory phenotype in the absence of stimulation is consistent with a priming effect of mutant huntingtin, whereby basal dysfunction leads to an exaggerated inflammatory response once a stimulus is encountered. These data advance our understanding of mutant huntingtin pathogenesis, establish resting myeloid cells as a key source of HD immune dysfunction, and further demonstrate the importance of systemic immunity in the potential treatment of HD and the wider study of neurodegeneration.
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: James R C
authors.initials: JR
authors.lastname: Miller
authors.affiliation: UCL Genetics Institute, University College London, London, WC1E 6BT, UK.
authors.forename: Kitty K
authors.initials: KK
authors.lastname: Lo
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Ralph
authors.initials: R
authors.lastname: Andre
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Davina J
authors.initials: DJ
authors.lastname: Hensman Moss
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Träger
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Stone
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: UCL Genetics Institute, University College London, London, WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK s.tabrizi@ucl.ac.uk.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000071058:Huntingtin Protein / Q000096:biosynthesis / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D000071058:Huntingtin Protein; C508600:IL6 protein, human; D015850:Interleukin-6; D009419:Nerve Tissue Proteins