Biology subjects

Rombach, D.

Publications and source records attributed to Rombach, D..

3 recordsLinked to original sources

bioRxiv2026

Dysregulated splenic glucocorticoid sensitivity in aging and an α-synuclein transgenic mouse model of Parkinson's disease

Introduction: Parkinson's disease (PD) and aging both disrupt hypothalamic-pituitary-adrenal (HPA) axis function and peripheral immune homeostasis. Whether aging or -synuclein (-syn) pathology alters glucocorticoid (GC) sensitivity of peripheral immune cells has not been investigated. Methods: Using an ex vivo GC sensitivity assay, we assessed the responsiveness of isolated and lipopolysaccharide (LPS)-stimulated splenocytes to the anti-inflammatory effects of increasing doses of corticosterone (CORT) in a wild-type (WT) aging cohort and in a PD -syn transgenic mouse model and respective age-matched controls. Results: Compared with splenocytes from 6-month-old WT mice, splenocytes from 20-month-old WT mice were less sensitive to 0.1 and 0.5 M CORT. Isolated splenocytes from PD vs. control mice were less sensitive to 0.05, 0.1, and 0.5 M CORT specifically at 16 months of age, but not at 6 or 20 months of age. As peripheral immune phenotyping revealed neither differences in HPA axis-related parameters nor in splenic GC receptor expression between PD and age-matched control mice at 6, 16, and 20 months, splenic GC resistance in PD mice at 16 months of age seems to be mediated by downstream GR signaling dysfunction. Conclusion: Together, our results support the hypothesis that -syn pathology accelerates an aging-associated decline in the peripheral sensitivity to anti-inflammatory GCs and may thereby sustain systemic and neuroinflammatory processes in PD.

neuroscience↗

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2025

Spreading alpha-Synuclein Oligomers Trigger Astrocyte Reactivity and Astrocyte-glutamatergic Neuron system dysfunction in an Age-Dependent Manner

BackgroundParkinsons disease (PD) is characterized by the progressive accumulation and spatio-temporal spread of -synuclein (-syn) oligomers and a progressive loss of dopaminergic neurons. Many studies showed a direct cytotoxic effect of -syn oligomers on neurons. Other cell types including astrocytes were also reported to show specific responses to -syn and are believed to play a role in the spreading of PD pathology. MethodsTo investigate the transcriptional and cellular consequences of -syn oligomer spreading, we employed spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a transgenic PD mouse model expressing human -syn in neurons. We further compared our findings to published public snRNA-seq datasets from human PD patients ResultsOur analysis identified -syn spreading mostly to the substantia nigra and defined a transcriptional "Spreading Signature" associated with -syn pathology. We found an age correlated increase in astrocytes, close interactions between astrocytes and -syn, and transcriptional dysregulation of the astrocyte-glutamatergic neuron axis. We further identified two subtypes of glutamatergic neurons that are vulnerable to astrocytic changes. Comparative analysis with human PD snRNA-seq data showed concordant transcriptional changes related to astrocytic dysfunctions and diminished neuronal signaling. ConclusionBased on our results, we propose a model of -syn oligomer spreading involving astrocytes, glutamatergic synapses, and a disturbance in the astrocyte-glutamatergic neuron axis.

neuroscience↗