Billheimer, D. | bioRxiv Science

bioRxiv2025

Acute E2/P4 loss compromises the biology and function of neurogenic niches during a vulnerable female aging period

Effects of aging on neural stem progenitor cells (NSPCs) have been studied in males, but less is known in females. Here we comparatively assess female NSPC biology, both in the subventricular zone and hippocampal dentate gyrus niches, across different ages of F344 rats (2, 6, 9 and 14 months). The rats were ovariectomized (OVX) or remained Intact at each of the aging stages, to assess the role of the female sex hormones, estradiol (E2) and progesterone (P4). Results show that while age-dependent decays become prominent at 14 months, ovariectomy-induced E2/P4 loss markedly reduces neurogenesis and associated behavioral function, earlier, at 9 months of age. Coinciding with this pattern of neurogenic decline, we also detect adaptive changes in estrogen and progesterone receptor expression, antioxidant expression, and brain E2/P4 levels. Fundamentally, these results reveal specific female time-periods, when the brain is sensitive to age and E2/P4 loss, potentially setting-up for disease susceptibility.

neuroscience↗

bioRxiv2023

Parallel Neurodegenerative Phenotypes in Sporadic Parkinsons Disease Fibroblasts and Midbrain Dopamine Neurons

Understanding the mechanisms causing Parkinsons disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they also differed in their nature and scale. Furthermore, statistical analysis revealed novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments.

neuroscience↗