ABSTRACT
Ubiquitin ligases control the degradation of core clock proteins to govern the speed and resetting properties of the circadian pacemaker. However, few studies have addressed their potential to regulate other cellular events within clock neurons beyond clock protein turnover. Here, we report that the ubiquitin ligase, UBR4/POE, strengthens the central pacemaker by facilitating neuropeptide trafficking in clock neurons and promoting network synchrony. Ubr4-deficient mice are resistant to jetlag, whereas poe knockdown flies are prone to arrhythmicity, behaviors reflective of the reduced axonal trafficking of circadian neuropeptides. At the cellular level, Ubr4 ablation impairs the export of secreted proteins from the Golgi apparatus by reducing the expression of Coronin 7, which is required for budding of Golgi-derived transport vesicles. In summary, UBR4/POE fulfills a conserved and unexpected role in the vesicular trafficking of neuropeptides, a function that has important implications for circadian clock synchrony and circuit-level signal processing.
Subject(s)
Circadian Clocks , Drosophila Proteins , Neuropeptides , Animals , CLOCK Proteins/metabolism , Calmodulin-Binding Proteins/metabolism , Circadian Clocks/genetics , Circadian Rhythm , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Mice , Neuropeptides/genetics , Neuropeptides/metabolism , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/metabolismABSTRACT
INTRODUCTION: Changes to federal legislation allowed nicotine-based e-cigarettes legal entry into the Canadian market in 2018. This included pod-type e-cigarettes (pods), such as JUUL, that were later found to be associated with steeply increasing prevalence and greater frequency of e-cigarette use among US and Canadian youth. Multiple studies of risk factors of JUUL use and use initiation have been conducted among various population groups in the US, but little evidence exists pointing to similar risk factors of pod use among Canadian youth and young adults. Understanding these risk factors can inform use prevention and intervention strategies in Canadian and other jurisdictions. METHODS: A total of 668 Canadian youth and young adults recruited by the 2018-19 Youth and Young Adult Panel Study were provided a baseline survey 3 months before and a follow-up survey 9 months after the relaxation of federal nicotine e-cigarette regulations. We used multivariable logistic regression to understand and rank importance of baseline predictors of future pod use among respondents. RESULTS: Past-month cannabis use (OR [odds ratio] = 2.66, 95% CI: 1.66-4.21, p < 0.001), established cigarette use (OR = 3.42, 1.53-7.65, p < 0.01), past cigarette experimentation (OR = 2.40, 1.34-4.31, p < 0.01), having many friends who vaped (OR = 2.15, 1.37-3.34, p < 0.001), age below 18 compared to age over 22 (OR = 5.26, 2.63-10.00, p < 0.001) and male sex (OR = 1.69, 1.16-2.50, p < 0.01) were significant and the most influential predictors of future pod use. CONCLUSION: Similar factors drove pod use among Canadian and US youth and young adults. Appropriate preventive strategies can benefit from considering polysubstance use among high school-aged youth.
