Biology subjects

Kiechle, M.

Publications and source records attributed to Kiechle, M..

3 recordsLinked to original sources

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

High-throughput Mucus Microrheology for Phenotyping and Disease Modeling

Mucus mechanics regulate barrier, clearance, and transport functions across epithelial tissues, yet quantitative rheology remains difficult to scale because available assays require large volumes, specialized equipment, or extensive manual analysis. Here, a high-throughput microrheology workflow based on Differential Dynamic Microscopy is established for frequency-dependent measurements from 3-10 uL mucus samples and intact mucosal surfaces using standard epifluorescence microscopy. The workflow combines preloaded tracer chambers, controlled sample handling, short video acquisition, and automated analysis to reduce operator intervention while preserving sensitivity to mucus relaxation on 1--20 s time scales. Validation against shear rheometry and particle tracking in reconstituted mucin gels shows robust recovery of viscoelastic trends across mucus-like material states. Applications in human airway epithelial air--liquid interface cultures resolve culture-medium, age, donor, COPD, cigarette-smoke, cystic-fibrosis treatment, and IL-13-associated differences, including spatial heterogeneity in situ. Measurements of clinical cervical mucus further demonstrate parallel testing of scarce specimens and sensitivity to osmotic swelling. This platform provides a scalable route to quantitative mucus phenotyping for disease modeling, therapeutic testing, and future precision-medicine studies.

bioengineering↗