Identification and structural analysis of C-terminally truncated collapsin response mediator protein-2 in a murine model of prion diseases

<p>Abstract</p> <p>Background</p> <p>Prion diseases are fatal neurodegenerative disorders that accompany an accumulation of the disease-associated form(s) of prion protein (PrP^Sc) in the central nervous system. The neuropathological changes in the brain begin with focal deposits of PrP^Sc, followed by pathomorphological abnormalities of axon terminal degeneration, synaptic loss, atrophy of dendritic trees, and eventual neuronal cell death in the lesions. However, the underlying molecular basis for these neuropathogenic abnormalities is not fully understood.</p> <p>Results</p> <p>In a proteomic analysis of soluble proteins in the brains of mice challenged intracerebrally with scrapie prion (Obihiro I strain), we found that the amount of the full-length form of collapsin response mediator protein-2 (CRMP-2; 61 kDa) decreased in the late stages of the disease, while the amount of its truncated form (56 kDa) increased to comparable levels observed for the full-length form. Detailed analysis by liquid chromatography-electrospray ionization-tandem mass spectrometry showed that the 56-kDa form (named CRMP-2-ΔC) lacked the sequence from serine⁵¹⁸to the C-terminus, including the C-terminal phosphorylation sites important for the regulation of axonal growth and axon-dendrite specification in developing neurons. The invariable size of the mRNA transcript in Northern blot analysis suggested that the truncation was due to post-translational proteolysis. By overexpression of CRMP-2-ΔC in primary cultured neurons, we observed the augmentation of the development of neurite branch tips to the same levels as for CRMP-2^T514A/T555A, a non-phosphorylated mimic of the full-length protein. This suggests that the increased level of CRMP-2-ΔC in the brain modulates the integrity of neurons, and may be involved in the pathogenesis of the neuronal abnormalities observed in the late stages of the disease.</p> <p>Conclusions</p> <p>We identified the presence of CRMP-2-ΔC in the brain of a murine model of prion disease. Of note, C-terminal truncations of CRMP-2 have been recently observed in models for neurodegenerative disorders such as ischemia, traumatic brain injury, and Wallerian degeneration. While the structural identity of CRMP-2-ΔC in those models remains unknown, the present study should provide clues to the molecular pathology of degenerating neurons in prion diseases in connection with other neurodegenerative disorders.</p

Risk of obstructive sleep apnea and excessive daytime sleepiness in hospitalized psychiatric patients

Farid R Talih,1 Jean J Ajaltouni,1 Hani M Tamim,2 Firas H Kobeissy3 1Department of Psychiatry, 2Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 3Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Objectives: This study evaluated the risk of developing obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) in hospitalized psychiatric patients at the American University of Beirut Medical Center (AUB-MC). Factors associated with OSA and EDS occurrence in this sample were also examined. Methods: The Berlin questionnaire and the Epworth sleepiness scale; which respectively evaluate OSA and EDS symptoms, were administered to individuals hospitalized at an acute psychiatric treatment unit at the AUB-MC between the dates of January 2014 and October 2016. Additional data collected included general demographics, psychiatric diagnoses, and questionnaires evaluating depression and anxiety symptoms. Statistical analyses utilizing SPSS were performed to determine the prevalence of OSA and EDS, as well as their respective associations with patient profiles. Results: Our results showed that 39.5% of participants were found to have a high risk of sleep apnea and 9.9% of the participants were found to have abnormal daytime sleepiness. The risk of developing OSA was associated with a higher body mass index (BMI) (P=0.02), and depression severity (patient health questionnaire 9 score) (P=0.01). Increasing severity of depressive symptoms was associated with a higher risk of sleep apnea (P=0.01). BMI (odds ratio [OR] =5.97, 95% confidence interval [CI] 1.89&ndash;18.82) and depression severity (OR =4.04, 95% CI 1.80&ndash;9.07) were also found to be predictors of OSA. The psychiatric diagnoses of the participants were not found to have a significant association with the risk of sleep apnea. Conclusion: The risk of OSA is increased among hospitalized psychiatric patients, and this condition can have detrimental effects on psychiatric patients. OSA appears to be under-recognized in this population, psychiatrists should screen for OSA in hospitalized psychiatric patients and refer them for diagnostic testing or treatment when indicated. Keywords: obstructive sleep apnea, excessive daytime sleepiness, depression, anxiety, psychiatric patients, inpatient psychiatr