Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: Insights from a transgenic mouse model

Abstract

Sleep disorders are nearly ubiquitous among patients with Parkinson’s disease (PD), and they manifest early in the disease process. While there are a number of possible mechanisms underlying these sleep disturbances, a primary dysfunction of the circadian system should be considered as a contributing factor. Our laboratory’s behavioral phenotyping of a well-validated transgenic mouse model of PD reveals that the electrical activity of neurons within the master pacemaker of the circadian system, the suprachiasmatic nuclei (SCN), is already disrupted at the onset of motor symptoms, although the core features of the intrinsic molecular oscillations in the SCN remain functional. Our observations suggest that the fundamental circadian deficit in these mice lies in the signaling output from the SCN, which may be caused by known mechanisms in PD etiology: oxidative stress and mitochondrial disruption. Disruption of the circadian system is expected to have pervasive effects throughout the body and may itself lead to neurological and cardiovascular disorders. In fact, there is much overlap in the non-motor symptoms experienced by PD patients and in the consequences of circadian disruption. This raises the possibility that the sleep and circadian dysfunction experienced by PD patients may not merely be a subsidiary of the motor symptoms, but an integral part of the disease. Furthermore, we speculate that circadian dysfunction can even accelerate the pathology underlying PD. If these hypotheses are correct, more aggressive treatment of the circadian misalignment and sleep disruptions in PD patients early in the pathogenesis of the disease may be powerful positive modulators of disease progression and patient quality of life.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention

“…-Sleep disorders [delayed sleep phase syndrome (Skene et al, 1999), non-24 h sleep/ wake disorder and sleep/wake schedule disorder (Dagan & Abadi, 2001;Uchiyama & Lockley, 2015), recurrent hypersomnia (Billiard et al, 2011), SW sleep disorder (Schwartz & Roth, 2006)] -SW intolerance (Andlauer & Reinberg, 1979;Reinberg et al, 1983Reinberg et al, , 1988) -Delirium (Fitzgerald et al, 2013) -Peptic ulcer disease (Moore & Merki, 1997;Moore & Smolensky, 1991) -Affective disorders [depression (BicakovaRocher et al, 1996;Rosenwasser & WirtzJustice, 1997;Salgado-Delgado et al, 2011), mania (Klemfuss & Kripke, 1989), bipolar disorder (Abreu & Bragança, 2015)] -Parkinson's disease (Bordet et al, 2003;Fertl et al, 1991;Willison et al, 2013) -Autism spectrum disorder (Botbol et al, 2013;Tordjman et al, 2015) -Smith-Magenis syndrome (Chen et al, 2015) -Fatal familial insomnia [autosomal dominant prion brain disease (Montagna et al, 1995;Portaluppi et al, 1994aPortaluppi et al, , 1994bPortaluppi et al, , 1995] -Kidney failure, especially end-stage disease (Biasioli et al, 1988;Farfel et al, 1978;Hillier et al, 1980;Koch et al, 2009;Mojón et al, 2013;Portaluppi et al, 1990;Raff & Trivedi, 2012;Russcher et al, 2015;Wheatley et al, 1989) -Pulm...…”

The Molecular Mechanism of Intestinal Levodopa Absorption and Its Possible Implications for the Treatment of Parkinson’s Disease

“…Parkinson patients develop several nonmotor symptoms with a diurnal component, suggesting circadian dysfunction (Kallio et al, 2000;Buijs et al, 2003;Willison et al, 2013). Orally administered levodopa is usually delivered throughout the day in several doses because the absorption of the drug was shown to be faster during the daytime (Nyholm et al, 2010).…”

How to fix a broken clock

“…Therefore, targeting and strengthening circadian function may prove beneficial for other symptoms of the disease. Mouse models of these diseases indicate that the circadian system is impacted [80–85] and are helping uncover the cause of disruption.…”