Abstract
Exposure to early-life stress (ELS) can persistently modify neuronal circuits and functions, and contribute to the expression of misfolded and aggregated proteins that are hallmarks of several neurodegenerative diseases. The healthy brain is able to clear dysfunctional proteins through the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Accumulating evidence indicates that impairment of these pathways contributes to enhanced protein aggregation and neurodegeneration. While stress is a known precipitant of neurological decline, few specific mechanistic links underlying this relationship have been identified. We hypothesized that neonatal maternal separation (MatSep), a well-established model of ELS, has the ability to alter the levels of UPS and ALP components in the brain, and thus has the potential to disrupt proteostasis. The expression of proteostasis-associated protein markers was evaluated by immunoblotting in the hippocampus and cortex of adult Wistar rats that were previously subjected to MatSep. We observed multiple sex- and MatSep-specific changes in the expression of proteins in the ALP, mitophagy, and UPS pathways, particularly in the hippocampus of adult animals. In contrast, MatSep had limited influence on proteostasis marker expression in the cortex of adult animals. Our results indicate that MatSep can selectively modify the intracellular protein degradation machinery in ways that may impact the development and progression of neurodegenerative disease.
Highlights
Life stress (ELS) has been demonstrated to exert profound physiological effects with long-lasting consequences on human health (Lai and Huang, 2011)
We assessed whether sex differences or maternal separation (MatSep)-induced changes were observed in aged animals, utilizing one-way analysis of variance (ANOVA) with Bonferroni post hoc analysis
The results presented here demonstrate that MatSep is sufficient to induce changes in the expression of multiple protein markers of the autophagy-lysosomal pathway (ALP), mitophagy, and ubiquitin-proteasome system (UPS) pathways, while providing evidence that MatSep can induce differential effects based on sex, brain region, and age
Summary
Life stress (ELS) has been demonstrated to exert profound physiological effects with long-lasting consequences on human health (Lai and Huang, 2011). This, in turn, has been associated with increased brain vulnerability to neurodegenerative processes (Esch et al, 2002; Brunson et al, 2005; Oomen et al, 2010; Hoeijmakers et al, 2018). This neuroendocrine imbalance is known to be present in patients with neurodegenerative conditions, such as Alzheimer’s and Parkinson’s diseases (Huang et al, 2009; Ros-Bernal et al, 2011), the specific mechanisms that underlie the highly complex ELS-neurodegeneration relationship are still poorly understood. We have more thoroughly investigated the possible contributions of abnormal protein aggregation by examining the effects of neonatal maternal separation (MatSep), a model of ELS, on the expression of protein markers of proteostasis in the brain
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
