Abstract
Background: Most neurodegenerative diseases are sporadic and develop with age. Degenerative neural tissues often contain intra- and extracellular protein aggregates, suggesting that the proteostasis network that combats protein misfolding could be dysfunctional in the setting of neurodegenerative disease. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is crucial for protein folding and modulating the adaptive response in early secretory pathways. The interaction between BiP and unfolded proteins is mediated by the substrate-binding domain and nucleotide-binding domain with ATPase activity. The interaction facilitates protein folding and maturation. BiP has a recovery motif at the carboxyl terminus. The aim of this study is to examine cognitive function in model mice with an impaired proteostasis network by expressing a mutant form of BiP lacking the recovery motif. We also investigated if impairments of cognitive function were exacerbated by exposure to environmental insults, such as inhaled anesthetics.Methods: We examined cognitive function by performing radial maze testing with mutant BiP mice and assessed the additional impact of general anesthesia in the context of proteostasis dysfunction. Testing over 8 days was performed 10 weeks, 6 months, and 1 year after birth.Results: Age-related cognitive decline occurred in both forms of mice. The mutant BiP and anesthetic exposure promoted cognitive dysfunction prior to the senile period. After senescence, when mice were tested at 6 months of age and at 1 year old, there were no significant differences between the two genotypes in terms of the radial maze testing; furthermore, there was no significant difference when tested with and without anesthetic exposure.Conclusion: Our data suggest that aging was the predominant factor underlying the impairment of cognitive function in this study. Impairment of the proteostasis network may promote age-related neurodegeneration, and this is exacerbated by external insults.
Highlights
Synthesized polypeptides destined for secretory proteins and transmembrane proteins are inserted into the endoplasmic reticulum (ER) and monitored by the proteostasis network
Radial maze testing was used to evaluate how cognitive functions were affected by aging in the setting of proteostasis dysfunction
In wild-type mice, the completion time was shortest at 10 weeks after birth and significantly longer at 1 year (P < 0.01)
Summary
Synthesized polypeptides destined for secretory proteins and transmembrane proteins are inserted into the endoplasmic reticulum (ER) and monitored by the proteostasis network. Folded proteins are degraded, or sequestered as aggregates inside and outside the cell, leading to stress responses such as the unfolded protein response in the ER (Ron and Walter, 2007) and the heat shock response in the cytosol (Brandvold and Morimoto, 2015; Balchin et al, 2016), which increases the capacity of the proteostasis network. Failure of this response causes cellular dysfunction and cell death in various human diseases (Walter and Ron, 2011). We investigated if impairments of cognitive function were exacerbated by exposure to environmental insults, such as inhaled anesthetics
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
