Biology subjects

Sondermann, J. R.

Publications and source records attributed to Sondermann, J. R..

8 recordsLinked to original sources

bioRxiv2026

History of opioid use disorder correlates with altered neuroimmune signatures in the human dorsal root ganglia

Understanding mechanisms for the negative reinforcing effects of opioids are fundamental to improving patient care. Using human dorsal root ganglia (DRG) from donors with and without opioid use disorder (OUD), we set out to examine functional and molecular correlates of chronic opioid use. At a molecular level, we detected disrupted immune signatures throughout cells in the peripheral nervous system (PNS), spanning glial-neuroimmune interactions to changes in non-neuronal senescence. At the physiological level these changes are paired with sensitization of DRG sensory neurons. Our findings reveal a neuro-inflammatory state in the PNS of individuals with OUD. Targeting therapeutics towards these PNS-based mechanisms could be an approach to alleviating the negative reinforcing effects of opioids.

neuroscience↗

bioRxiv2026

Progressive neurodegeneration in human dorsal root ganglion from diabetes to painful neuropathy

Diabetic painful neuropathy (DPN) is characterized by neuropathic pain accompanied by loss of sensory function. We hypothesized that neurodegeneration in the dorsal root ganglion (DRG) could underlie DPN progression. To address this question, we performed multi-omic evaluation on DRGs from otherwise healthy organ donors, donors with diabetes but no neuropathy, and donors with clinically diagnosed DPN. We discovered that the first stages of neurodegeneration begin early in diabetes before the onset of DPN, with Nageotte nodule formation accompanied by apoptotic gene expression and decreased proportion of specific populations of A-fibers in DPN with remodeling of non-neuronal cells. Our findings define DPN as a neurodegenerative disorder of the DRG, identify molecular markers of disease stage, and highlight the need for early intervention to prevent irreversible neurodegeneration.

neuroscience↗

bioRxiv2025

Proximity labelling reveals the compartmental proteome of murine sensory neurons

IntroductionUnderstanding the molecular architecture of peripheral sensory neurons is critical as we pursue novel drug targets against pain and neuropathy. Sensory neurons in the dorsal root ganglion (DRG) show extensive compartmentalization, thus understanding each compartment - from the peripheral to central terminals - is key to this effort. MethodsTo systematically profile this spatial complexity, we generated a TurboIDfl/fl transgenic mouse line (ROSA26em1(TurboID)Bros), enabling targeted proximity labelling and deep proteomic profiling of DRG neuron compartments via Tg(Advillin-Cre)+. ResultsOur data reveal distinct proteomic signatures across neuronal compartments that reflect specialized neuronal functions. We provide proteomic insights into previously inaccessible nerve terminals both in the periphery (innervating the skin) and in the spinal cord. Further, using a DRG explant model of chemotherapy-induced peripheral neuropathy, we uncover novel and discrete proteome changes, highlighting neuronal vulnerability. ConclusionTogether, our findings provide a unique proteome atlas of the sensory neuron proteome across anatomical domains and demonstrate the utility of proximity labelling proteomics for detecting compartment-specific molecular alterations in a disease model.

neuroscience↗

bioRxiv2024

Multi-omic integration with human DRG proteomics highlights TNFα signalling as a relevant sexually dimorphic pathway

The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNF signalling emerging as a key sexually dimorphic pathway with higher prominence in males. Genetic evidence from genome-wide association studies (GWAS) further supports the functional relevance of TNF signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNF inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.

neuroscience↗

bioRxiv2023

Expanding the Characterization of Microbial Ecosystems using DIA-PASEF Metaproteomics

Metaproteomics is gaining momentum in microbiome research due to the multi-dimensional information it provides. However, current approaches have reached their detection limits. We present a highly-sensitive metaproteomic workflow using the extra information captured by Parallel Accumulation-Serial Fragmentation (PASEF) technology. The comparison of different acquisition modes and data analysis software packages showed that DIA-PASEF and DIA-NN doubled protein identifications of mouse gut microbiota and, importantly, also of the host proteome. DIA-PASEF significantly improved peptide detection reproducibility and quantification accuracy, which resulted in more than twofold identified taxa, reaching depths comparable to metagenomic studies. Consequently, DIA-PASEF exhibited improved coverage of functional networks revealing 131 additional pathways compared to DDA-PASEF. We applied our optimized workflow to a pre-clinical mouse model of chronic pain, in which we deciphered novel host-microbiome interactions. In summary, we present here a metaproteomic approach that paves the way for increasing the functional characterization of microbiome ecosystems and is applicable to diverse fields of biological research.

microbiology↗

bioRxiv2022

Transcriptomic and proteomic profiling of NaV1.8-expressing mouse nociceptors

Nociceptors play an essential role in both acute pain and chronic pain conditions. and have recently been classified into distinct subsets using single-cell transcriptional profiling. In this study, we examined protein levels in dorsal root ganglia using DIA Mass-spectrometry technologies with NaV1.8Cre+/-; ROSA26-flox-stop-flox-DTA (Diphtheria toxin fragment A) mutant mice (NaV1.8Cre-DTA), in which NaV1.8-expressing neurons (mainly nociceptors) in dorsal root ganglia (DRG) were ablated. The results show that 353 transcripts and 78 proteins, including nociceptor-specific sodium channels NaV1.8 (Scn10a) and NaV1.9 (Scn11a), were specifically expressed in nociceptors of DRG. A comparative analysis revealed that about 40% of nociceptor-specific proteins are shared within the nociceptor-specific transcript dataset. Scatter plots show that the proteome and transcriptome datasets in nociceptors have a moderate correlation (r = 0.4825), indicating the existence of post-transcriptional and post-translational gene regulation in nociceptors. This combined profiling study provides a unique resource for sensory studies, especially for pain research.

neuroscience↗

bioRxiv2022

Deep Proteome Profiling Reveals Signatures of Age and Sex Differences in Paw Skin and Sciatic Nerve of Naïve Mice

The age and sex of studied animals profoundly impact experimental outcomes in animal-based preclinical biomedical research. However, most preclinical studies in mice use a wide-spanning age range from 4 to 14 weeks and do not assess study parameters in male and female mice in parallel. This raises concerns regarding reproducibility and neglects potentially relevant age and sex differences. Furthermore, the molecular setup of tissues in dependence of age and sex is unknown in naive mice. Here, we employed an optimized quantitative proteomics workflow in order to deeply profile mouse paw skin and sciatic nerve (SCN) - two tissues, which are crucially implicated in nociception and pain as well as diverse diseases induced by inflammation, trauma, and demyelination. Remarkably, we uncovered significant differences when comparing (i) male and female mice, and, in parallel, (ii) adolescent mice (4 weeks) with adult mice (14 weeks). Age was identified as a major discriminator of analyzed samples irrespective of tissue type. Moreover, our analysis enabled us to decipher protein subsets and networks that exhibit differential abundance in dependence on the age and/or sex of mice. Notably, among these were proteins and signaling pathways with known relevance for (patho)physiology, such as homeostasis and epidermal signaling in skin and, in SCN, multiple myelin proteins and regulators of neuronal development. In addition, extensive comparisons with available databases revealed that we quantified approx. 50% of gene products that were implicated in distinct skin diseases and pain, many of which exhibited significant abundance changes in dependence on age and/or sex. Taken together, our study emphasizes the need for accurate age matching and uncovers hitherto unknown sex and age differences at the level of proteins and protein networks. Overall, we provide a unique systems biology proteome resource, which facilitates mechanistic insights into somatosensory and skin biology in dependence on age and sex - a prerequisite for successful preclinical studies in mouse disease models. Graphic workflow O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/498721v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@fc5aaforg.highwire.dtl.DTLVardef@1a5b87dorg.highwire.dtl.DTLVardef@f353e9org.highwire.dtl.DTLVardef@109f6e5_HPS_FORMAT_FIGEXP M_FIG C_FIG The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

systems biology↗

bioRxiv2022

Species-specific cutaneous protein signatures upon incision injury and correlation with distinct pain-related phenotypes in humans

Pain after surgery is common, and its management remains a clinical challenge. Severe acute and prolonged post-surgical pain impairs immediate recovery and leads to long-term consequences like chronic pain, opioid dependency, and reduced quality of life. Althought rodent pain incision models exist, translation to patients is still hampered. To bridge this gap, we combined sensory phenotyping with quantitative proteomics and protein networks in humans and mice after skin incision representing an established model for surgical pain. Initially, we revealed, for the first time, similarities and differences of protein-protein interaction (PPI) networks across both species. Next, we comprehensively phenotyped humans for pain-related symptoms and observed phenotypes with incision-induced proteome changes. Remarkably, post-incision PPI-networks differed between volunteers with small incision-related hyperalgesic areas ("Low responder") versus those with large areas ("High responder"). The latter exhibited a pronounced proteolytic environment associated with persistent inflammation, while an anti-inflammatory protein signature was observed in Low responders. Taken together, we provide unprecedented insights into peripheral processes relevant for developing hyperalgesia and pain after incision. This knowledge will immensely facilitate bidirectional translational pain studies and guide future research on the pathophysiology of pain after surgery and the discovery of novel targets for its treatment and prevention.

neuroscience↗