Biology subjects

Arendt-Tranholm, A.

Publications and source records attributed to Arendt-Tranholm, A..

5 recordsLinked to original sources

bioRxiv2025

A Reference Atlas of the Human Dorsal Root Ganglion

Somatosensory perception largely emerges from diverse peripheral sensory neurons whose cell bodies reside in dorsal root ganglia (DRG). Damage or dysfunction of DRG neurons is a major cause of chronic pain and sensory loss. In mice, deep single-cell transcriptomic profiling and genetically defined models have offered important clues into DRG function, but in humans, the cellular and molecular landscape of DRG neurons remains less understood. Here, we constructed a reference cell atlas of the human DRG by profiling transcriptomes of cells and nuclei from 126 donors sampled across cervical, thoracic, and lumbar DRGs. This atlas resolves 22 neuronal subtypes, including known and previously unrecognized subtypes linked to nociception, mechanosensation, thermosensation, and proprioception, as well as 10 types of non-neuronal cells. Cross-species integration, spatial transcriptomics, and microneurography enabled cell-type-specific comparisons of soma size and conduction velocity between species. Human DRG somata are larger across all cell types than their mouse counterparts, and the conduction velocities of human hair follicle innervating A-fibers are faster than in mice, suggesting a functional shift in rapid mechanical detection in humans. This integrated human DRG reference cell atlas provides a resource for exploring new molecular and physiological features of human DRG, which could help identify new strategies for treating chronic pain and other diseases of the peripheral nervous system.

neuroscience↗

bioRxiv2025

Peripheral nerve-targeting and pain-promoting transcriptomic signatures in early Guillain-Barr&eacute syndrome

Guillain-Barre syndrome (GBS) is an autoimmune disorder that causes weakness, sensory loss, autonomic dysfunction, and chronic neuropathic pain. The mediators responsible for driving early autoimmune injury in the most common GBS variant, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), remain incompletely understood. We performed single-cell and bulk RNA sequencing on peripheral blood mononuclear cells collected from early untreated AIDP-variant GBS patients and healthy controls to comprehensively deduce leukocyte transcriptome alterations and predict disease- and pain-driving interactions between pathogenic leukocytes and peripheral nervous system cells. We found that classical, intermediate, and non-classical monocytes were expanded and upregulated genes associated with type I and II interferons, JAK/STAT signaling, and NLRP3 inflammasome engagement. CD8+ T cells were highly proliferative and likewise upregulated JAK/STAT signaling. CD4+FOXP3+ regulatory T cells upregulated PRDM1 and CD74 in a signature that may indicate functional exhaustion. A subpopulation of highly activated intermediate monocytes upregulated genes related to angiogenesis and oncostatin M. Differential expression-based cell-cell interaction analysis between GBS leukocytes, Schwann cells, and sensory neurons predicted engagement of ligand-receptor pairs with nerve integrity and pain functions, including epiregulin, interferon-beta, adrenomedullin, clusterin, IL-6, IL-15, and CCL4. Functional validation demonstrated that CCL4 sensitizes human sensory neurons in vitro. These results unearth molecular interactions by which specific leukocyte populations in AIDP-variant GBS may participate in peripheral nerve injury and drive neuropathic pain. Many of these targets may be amenable to therapeutic modulation using available approved and investigational drugs, potentially providing drug repurposing opportunities.

neuroscience↗

bioRxiv2025

Conserved Axonal Transcriptome Dynamics Underlie PGE2-Induced Sensitisation and Identify Tnfrsf12a/Fn14 as a Regulator of Neuronal Excitability in DRG Neurons

Chronic pain arises when dorsal root ganglion (DRG) neurons become sensitised to noxious inputs, a process driven by inflammatory mediators such as prostaglandin E2 (PGE2). Local translation of axonal mRNAs is a key regulator of nociceptor plasticity, yet how axonal transcriptome dynamics contribute to inflammatory sensitisation remains unclear. Using compartmentalised culture systems and RNA-sequencing, we defined axonal and somatic transcriptomes in embryonic (E16.5) and adult (W8) DRG neurons and assessed their remodelling after PGE2 exposure. We identify a conserved core axonal transcriptome spanning embryonic to adult stages, prominently enriched for ribosomal and mitochondrial functions, consistent with sustained translational and metabolic demands. PGE2 elicited compartment-specific reprogramming: pathways related to sensory processing and pain were upregulated in axons but downregulated in somata. Functionally, prolonged axonal PGE2 exposure enhanced capsaicin-evoked Ca{superscript 2} responses and drove retrograde sensitisation of neuronal somata. Integrating transcriptomics with functional assays, we pinpointed Tnfrsf12a (Fn14), a cytokine receptor linked to regeneration and neuropathic pain, as a PGE2-induced axonal mRNA. Crucially, local axonal knockdown of Tnfrsf12a significantly reduced neuronal excitability, providing proof-of-concept that axonally enriched transcripts can be targeted to modulate sensitisation. These findings position conserved axonal transcriptome programmes as drivers of peripheral sensitisation and establish Tnfrsf12a as a therapeutic candidate for inflammatory pain.

neuroscience↗

bioRxiv2025

Single-cell characterization of the human C2 dorsal root ganglion recovered from C1-2 arthrodesis surgery: implications for neck pain

Neurons in the dorsal root ganglion (DRG) receive and transmit sensory information from the tissues they innervate and from the external environment. Upper cervical (C1-C2) DRGs are functionally unique as they receive input from the neck, head, and occipital cranial dura, the latter two of which are also innervated by the trigeminal ganglion (TG). The C2 DRG also plays an important role in neck pain, a common and disabling disorder that is poorly understood. Advanced transcriptomic approaches have significantly improved our ability to characterize RNA expression patterns at single-cell resolution in the DRG and TG, but no previous studies have characterized the C2 DRG. Our aim was to use single-nucleus and spatial transcriptomic approaches to create a molecular map of C2 DRGs from patients undergoing arthrodesis surgery with ganglionectomy. Patients with acute (<3 months) or chronic ([≥]3 months) neck pain were enrolled and completed patient-reported outcomes and quantitative sensory testing prior to surgery. C2 DRGs were characterized with bulk, single nucleus, and spatial RNA sequencing technologies from 22 patients. Through a comparative analysis to published datasets of the lumbar DRG and TG, neuronal clusters identified in both TG and DRG were identified in the C2 DRG. Therefore, our study definitively characterizes the molecular composition of human C2 neurons and establishes their similarity with unique characteristics of subsets of TG neurons. We identified differentially expressed genes in endothelial, fibroblast and myelinating Schwann cells associated with chronic pain, including FGFBP2, C8orf34 and EFNA1 which have been identified in previous genome and transcriptome wide association studies (GWAS/TWAS). Our work establishes an atlas of the human C2 DRG and identifies altered gene expression patterns associated with chronic neck pain. This work establishes a foundation for the exploration of painful disorders in humans affecting the cervical spine.

neuroscience↗

bioRxiv2023

RNA isoform expression landscape of the human dorsal root ganglion (DRG) generated from long read sequencing

Splicing is a post-transcriptional RNA processing mechanism that enhances genomic complexity by creating multiple isoforms from the same gene. Diversity in splicing in the mammalian nervous system is associated with neuronal development, synaptic function and plasticity, and is also associated with diseases of the nervous system ranging from neurodegeneration to chronic pain. We aimed to characterize the isoforms expressed in the human peripheral nervous system, with the goal of creating a resource to identify novel isoforms of functionally relevant genes associated with somatosensation and nociception. We used long read sequencing (LRS) to document isoform expression in the human dorsal root ganglia (hDRG) from 3 organ donors. Isoforms were validated in silico by confirming expression in hDRG short read sequencing (SRS) data from 3 independent organ donors. 19,547 isoforms of protein-coding genes were detected using LRS and validated with SRS and strict expression cutoffs. We identified 763 isoforms with at least one previously undescribed splice-junction. Previously unannotated isoforms of multiple pain-associated genes, including ASIC3, MRGPRX1 and HNRNPK were identified. In the novel isoforms of ASIC3, a region comprising [~]35% of the 5UTR was excised. In contrast, a novel splice-junction was utilized in isoforms of MRGPRX1 to include an additional exon upstream of the start-codon, consequently adding a region to the 5UTR. Novel isoforms of HNRNPK were identified which utilized previously unannotated splice-sites to both excise exon 14 and include a sequence in the 5 end of exon 13. The insertion and deletion in the coding region was predicted to excise a serine-phosphorylation site favored by cdc2, and replace it with a tyrosine-phosphorylation site potentially phosphorylated by SRC. We also independently confirm a recently reported DRG-specific splicing event in WNK1 that gives insight into how painless peripheral neuropathy occurs when this gene is mutated. Our findings give a clear overview of mRNA isoform diversity in the hDRG obtained using LRS. Using this work as a foundation, an important next step will be to use LRS on hDRG tissues recovered from people with a history of chronic pain. This should enable identification of new drug targets and a better understanding of chronic pain that may involve aberrant splicing events.

neuroscience↗