HSP40 overexpression in pacemaker neurons protects against circadian dysfunction in a Drosophila model of Huntington's Disease

Circadian disturbances are early features of neurodegenerative diseases, including Huntington's Disease (HD), affecting the quality of life of patients and caregivers. Emerging evidence suggests that circadian decline feeds-forward to neurodegenerative symptoms, exacerbating them, highlighting a need for restoring circadian health. Therefore, we asked whether any of the known neurotoxic modifiers can suppress circadian dysfunction. We performed a screen of neurotoxicity-modifier genes to suppress circadian behavioural arrhythmicity in a Drosophila circadian HD model. Notably, the molecular chaperones HSP40 and HSP70 (Heat Shock Protein) emerged as significant suppressors in the circadian context, with HSP40 being the more potent mitigator of HD-induced deficits. Upon HSP40 overexpression in the Drosophila circadian ventrolateral neurons (LNv), the behavioural rhythm rescue was associated with neuronal rescue of loss in circadian proteins from small LNv soma. Specifically, there was a restoration of the molecular clock protein Period and its oscillations in young flies and a long-lasting rescue of the output neuropeptide Pigment Dispersing Factor. Significantly, there was a reduction in the expanded Huntingtin inclusion load, concomitant with the appearance of a spot-like Huntingtin form. Thus, we provide evidence for the first time that implicates the neuroprotective chaperone HSP40 in circadian rehabilitation. Given the importance of proteostasis and circadian health in neurodegenerative diseases, the involvement of molecular chaperones in circadian maintenance has broader therapeutic implications.

Association of Night Shift Work With Chronic Spontaneous Urticaria and Effect Modification by Circadian Dysfunction Among Workers

Purpose: Night shift work is common in the current working environment and is a risk factor for many diseases. The study aimed to explore the relationship between night shift work with chronic spontaneous urticaria (CSU), and the modification effect of circadian dysfunction on it.Methods: A cross-sectional survey was conducted among Chinese workers. Exposure was measured by night work history and duration. Circadian dysfunction was characterized by excessive daytime sleepiness (EDS). The diagnosis of CSU was made by dermatologists who were investigating on the spot. The effect size was expressed as odds ratios (ORs).Results: A total of 8,057 participants were recruited, and 7,411 (92%) with complete information were included in the final analyses. The prevalence rates of CSU for workers without night shift and those with night shift history were 0.73 and 1.28%, respectively. Compared with workers who never worked night shifts, the risk of CSU increased with the length of night shift work: OR = 1.55 (95% confidence interval [CI]: 0.78–3.06) for duration <5 years and OR = 1.91 (95% CI: 1.12–3.26) for duration ≥5 years. EDS s EDS has been shown to modify this combination. Among workers without EDS, there was no association between night shift and CSU (OR = 0.94; 95% CI: 0.49–1.79). Whereas, in participants with EDS, the correlation was significant (OR = 3.58; 95% CI: 1.14–11.20). However, the effect modification by sleep disturbance was not observed.Conclusions: Night shift work is a risk factor for CSU, and there is a dose-response relationship between night shift work hours and the risk of CSU. This connection may be modified by circadian dysfunction.

Suppression of Circadian Timing and Its Impact on the Hippocampus

In this article, I describe the development of the disruptive phase shift (DPS) protocol and its utility for studying how circadian dysfunction impacts memory processing in the hippocampus. The suprachiasmatic nucleus (SCN) of the Siberian hamster is a labile circadian pacemaker that is easily rendered arrhythmic (ARR) by a simple manipulation of ambient lighting. The DPS protocol uses room lighting to administer a phase-advancing signal followed by a phase-delaying signal within one circadian cycle to suppress clock gene rhythms in the SCN. The main advantage of this model for inducing arrhythmia is that the DPS protocol is non-invasive; circadian rhythms are eliminated while leaving the animals neurologically and genetically intact. In the area of learning and memory, DPS arrhythmia produces much different results than arrhythmia by surgical ablation of the SCN. As I show, SCN ablation has little to no effect on memory. By contrast, DPS hamsters have an intact, but arrhythmic, SCN which produces severe deficits in memory tasks that are accompanied by fragmentation of electroencephalographic theta oscillations, increased synaptic inhibition in hippocampal circuits, and diminished responsiveness to cholinergic signaling in the dentate gyrus of the hippocampus. The studies reviewed here show that DPS hamsters are a promising model for translational studies of adult onset circadian dysfunction in humans.