Disorders of sleep and circadian rhythms.

Sleep is fundamental to the survival of humans. However, knowledge regarding the role of sleep and its regulation is poorly understood. Genetics in flies, mice, and humans has led to a detailed understanding of some aspects of circadian regulation. Sleep homeostasis (the effect of increasing periods of wakefulness on our sleep propensity) is largely not understood. Sleep homeostasis is distinct from, but also linked to, the circadian clock. It is only in the last two decades that our understanding of some sleep disorders has been revealed. These breakthroughs were mostly fueled by intensive investigation using genetic tools. Although modern human genetics has revolutionized scientific research of neurologic disorders beginning ~35 years ago, studies of sleep and sleep disorders have lagged behind those of many neurologic diseases. This is due to the complexity in phenotyping behaviors like sleep and the fact that sleep is strongly influenced by environmental and other factors. We have long been aware that the amount of sleep required by individuals is normally distributed in the general population with small proportions of people being natural short or natural long sleepers. However, it has been less than a decade since Mendelian families of natural short sleepers have been recognized. Recent work has made significant advances and mechanistic insights of several sleep disorders as well as familial natural short sleepers by using ever-improving human genetic and cellular molecular tools. Given recent advances into genetic and biologic understanding of sleep, the hope of understanding this indispensable process is closer. Ultimately, our growing understanding will lead to more effective treatments of human sleep disorders.

Acetylcholineestarase-inhibiting alkaloids from Lycoris radiata delay paralysis of amyloid beta-expressing transgenic C. elegans CL4176.

The limited symptom relief and side effects of current Alzheimer's disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid ß-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aß1-42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L' Her.) Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Aß-toxicity in C. elegans.