Biology subjects

Bopp, V.

Publications and source records attributed to Bopp, V..

5 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

Targeting CDC42 with CASIN Reprograms Cell-Type-Specific Transcriptomes and MAPK-Driven Transcription Factor Networks in the Aging Brain

BackgroundParkinsons disease (PD) is driven by -synuclein (-syn) aggregation and affects vulnerable dopaminergic and GABAergic neurons, and its incidence rises dramatically with age. In our -syn mouse model, motor impairment required both syn oligomers and the aging milieu, and pharmacological inhibition of the age hyperactivated Rho GTPase CDC42 with CASIN fully restored motor function, yet the underlying transcriptional pathways mediating this rescue remain to be elucidated. MethodsWe used an inducible -syn oligomer PD mouse model across three age groups (6, 16, and 24 months) with four conditions per group: -syn non-induced (OFF), induced (ON), and each with CASIN treatment (OFF-CASIN, ON-CASIN). Brain tissue from one hemisphere (0 to -5 mm Bregma) was sequenced using 10x Genomics 3 Chromium, with 3-4 mice per condition of both male and female mice. ResultssnRNA-seq demonstrated that CASIN robustly reverted PD-related transcriptional alterations at 24 months whereas aging-related changes were strongest at 16 months. Network and pathway analyses identified CASINs mode of action on two major downstream signaling cascades--MAPK and PI3K/AKT-- in the context of aging and MAPK signaling in PD. ConclusionConvergent gene-, transcription factor-, pathway-, and network-level evidence points to EGFR-PI3K-MAPK signaling as the axis through which CASIN may restore mitochondrial and synaptic function in PD and aging

neuroscience↗

bioRxiv2025

Molecular aging is the main driver of Parkinson's Disease

Aging as well as the presence of -synuclein (-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with -syn oligomers for the onset of PD symptoms remains unclear. Using an inducible -syn oligomer mouse model of PD, we demonstrate that the induction of PD associated -syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that -syn oligomer formation precedes motor decline in these aged mice, and age together with -syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of -syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the -syn model of PD.

neuroscience↗

bioRxiv2025

Monocyte Dysregulation Defines an MDD-Specific Transcriptional Signature Closely Linked to Clinical MDD Traits

ObjectiveMajor depressive disorder (MDD) is a highly heterogeneous psychiatric condition contributing significantly to the global disease burden. In a subset of MDD patients inflammatory processes accompany the disease and this has also been reported for other psychiatric conditions like schizophrenia (SZ). However, little is known regarding immune deregulation in relation to clinical symptoms. MethodsCellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of peripheral blood mononuclear cells (PBMCs) from patients with MDD (n=22), SZ (n=10), and healthy controls (HCs, n=26) was performed, yielding 633,284 high-quality single-cell profiles. Differential gene expression, cell composition, pathway enrichment, and weighted gene co-expression network analyses were conducted. MDD symptom severity was assessed using the Beck Depression Inventory-II (BDI-II), enabling the correlation of gene expression with individual disease symptoms. ResultsWe identified disease-specific transcriptomic signatures for MDD as well as for SZ and shared gene expression changes between the two conditions. For MDD, monocyte numbers were elevated concomitant with a strong enrichment of interferon signaling. The MDD-specific signature involving all peripheral cell types correlated strongly with key symptoms of depression like sadness or pessimism. Reactome analysis identified nuclear factor kappa-light-chain-enhancer of activated B cells (NF-{kappa}B)-associated pathways among the genes positively correlating with disease symptoms and traits. ConclusionOur findings might help to stratify psychiatric patients and provide a multidimensional framework for investigating immune contributions to psychiatric disorders and highlight potential targets for therapeutic intervention. Clinical symptoms might be reflected on a molecular level paving the way for more targeted and effective interventions.

genomics↗

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↗