👤 Nathalie Champagne

Animals in nature potentially experience multiple stressors, and those of anthropogenic origin are likely to be repeated or chronic. However, stress hormone levels are highly context-dependent and are not consistent predictors of chronic stress in wildlife. Profiling the downstream consequences of repeated stress responses, such as changes in metabolism or gene expression, may be more informative for predicting their individual-level health consequences and population-level impacts, which are key objectives for wildlife conservation. We previously found that in free-ranging juvenile elephant seals, the blubber transcriptome and proteome, but not cortisol levels, could distinguish between responses to single versus repeated stress axis stimulation. However, the blubber proteome response to stress was limited and mainly involved extra-cellular matrix proteins. In this study, we examined the plasma proteome response of four of the same animals to the repeated stress experiment, since multiple organs secrete proteins into the circulation, providing a readout of their activity and integration. We isolated plasma proteins, identified and quantified them using liquid chromatography and tandem mass spectrometry (LC-MS/MS) and compared their abundance between sampling times. We identified >200 proteins in plasma, of which 42 were altered in abundance, revealing complex protein dynamics in response to repeated stress challenges. These changes were delayed but sustained, suggesting that the plasma proteome may reflect longer term integration of multi-organ responses to recent, rather than immediate, challenges. Differentially abundant proteins included components of the osmoregulatory system, acute phase and complement proteins, organokines, apolipoproteins and hormone transport proteins, which coordinate physiological processes with significant implications for marine mammal health and may explain several aspects of marine mammal stress physiology, such as insulin resistance and high aldosterone levels. We identified several potentially novel biomarkers, such as AGT, HPX, TTR and APOA4, that may be useful for detecting recent and repeated stress exposure in marine mammals. Show less

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders. Show less