ReviewCircadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: Insights from a transgenic mouse model
Highlights
► Sleep disorders are common among PD patients and manifest early in the disease. ► α-Synuclein over-expressing (Thy1-aSyn) mice show circadian dysfunction. ► In Thy1-aSyn mice, the electrical output of the central clock is compromised. ► Circadian dysfunction may contribute to the pathology of PD.
Introduction
Epidemiological data indicates that sleep disorders are common in the developed world with an estimated 30 to 40% of the adult population reporting difficulty falling asleep at night and significant daytime sleepiness as a consequence (Hossain and Shapiro, 2002, Leger and Bayon, 2010, Luckhaupt et al., 2010, Roenneberg, 2012, Skaer and Sclar, 2010). These data suggest that many of us are all too familiar with the symptoms of sleep deprivation, including feelings of fatigue, irritability, reduced concentration, and reduced motor coordination (Acheson et al., 2007, Anderson and Platten, 2011, Durmer and Dinges, 2005, Louter et al., 2012). There is also a growing awareness that sleep deprivation is associated with metabolic imbalances and compromised immune response (Bechtold et al., 2010, Litinski et al., 2009, Mullington et al., 2009). These changes can occur even with transient sleep deprivation in which case they return to baseline with sufficient restorative sleep. Unfortunately, in chronically ill patients, restorative sleep is often permanently impaired. There is increasing evidence that in the case of neurodegenerative disorders, sleep disorders are extremely common, if not ubiquitous, and occur early in the disease progression (Chokroverty, 2009, Gagnon et al., 2008). These sleep disturbances predate the onset of the cognitive and motor symptoms and have significant negative consequences for both patients and caregivers, and if recognized, may facilitate earlier diagnosis and treatment.
Section snippets
Parkinson's disease (PD)
PD is the most common movement disorder among older adults, and is a leading cause of cognitive decline and dementia (Pontone et al., 2013, Williams-Gray et al., 2007). The classical triad of clinical features in PD consists of worsening resting tremor, rigidity, and bradykinesia. Pathologically, PD patients exhibit a progressive loss of dopaminergic neurons and the formation of Lewy bodies in the substantia nigra pars compacta (SNpc). Until relatively recently, it had been thought that it was
Sleep disorder are common in PD
Sleep disorders are extremely common in PD, with up to 90% of patients reporting primary insomnia, restless leg syndrome, hypersomnia, and rapid eye movement (REM) sleep disorder (Ferreira et al., 2006, Matsui et al., 2006, Stevens et al., 2004, Thorpy and Adler, 2005). These latter two syndromes of REM sleep disorder and hypersomnia appear to occur well in advance of the motor symptoms of PD (Abbott et al., 2005, Boeve, 2010, Boeve et al., 2007, Claassen et al., 2010, Iranzo, 2011, Iranzo et
Circadian system
In humans and other mammals, the circadian system is made up of a network of oscillators. The central clock is located in the suprachiasmatic nucleus (SCN). Neurons in this cell population receive light information from melanopsin-expressing retinal ganglion cells found in our retina. The axons of these ganglion cells make a direct synaptic connection onto cells in the SCN. These SCN neurons integrate this photic information with other timing cues to generate robust circadian oscillations that
Dysfunction in the circadian system may contribute to the etiology of the non-motor symptoms of PD
Several of the prominent non-motor symptoms of PD have a diurnal, temporal component that suggests an underlying circadian dysfunction. Most striking are the various types of sleep disruptions reported by PD patients: increased sleep latency, decreased sleep maintenance, fragmented sleep, and excessive daytime sleepiness. All of these symptoms may reflect alterations in the temporal patterning of sleep which often result from circadian dysfunction (Abbott et al., 2005, Dhawan et al., 2006,
Dopaminergic treatments for the core motor symptoms of PD may contribute to the disruption of the sleep/wake cycle
Central DA is generally associated with arousal and a variety of evidence suggests that this transmitter is involved in the regulation of the sleep/wake cycle at multiple circuits. Overall, levels of DA appear to exhibit low amplitude, daily rhythm in humans (Poceta et al., 2009) and in mice (Hampp et al., 2008). Centrally, DA levels are modulated by monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), which are key enzymes that regulate the catabolism of several different monoamine
Several models of PD show sleep and possible circadian disruption
The loss of DA neurons may play a role in the circadian disruption observed in non-human primates. One of the most developed models of PD involves treating primates with the toxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) which produces a set of symptoms that resemble PD (Fox and Brotchie, 2010) and can be treated with dopaminergic drugs. The MPTP-treated primates exhibit an immediate disruption of the sleep/wake cycle (Vezoli et al., 2011) as well as alteration in REM sleep and
α-Synuclein over-expressing mice as model of synucleinopathies, including PD
One of the best studied models of PD and other synucleinopathies is a line of transgenic mice expressing human α-synuclein (aSyn) under the Thy-1 promoter: the α-synuclein over-expressing (Thy1-aSyn) mice (Rockenstein et al., 2002). Genetic mutations in, and duplication of, α-synuclein are strongly associated with familial forms of PD; and polymorphisms in this gene are associated with increased PD risk (Cookson, 2009, Pankratz et al., 2009, Ritz et al., 2012, Simón-Sánchez et al., 2009,
Thy1-aSyn mice show selective deficits in circadian-regulated behavior, including the temporal distribution of sleep and activity
As measured by wheel running activity under either a standard 12 hour light and 12 hour dark cycle (LD), or under a continuous dark cycle (DD), the observed circadian cycle of all Thy1-aSyn mice initially appeared to be grossly rhythmic (Kudo et al., 2011b). However, the Thy1-aSyn mice exhibited fragmented, weak (low power) rhythms under both LD and DD conditions. These deficits are clearly illustrated when the mice are placed in a skeleton photoperiod consisting of two 1-h light exposures every
Other key circadian parameters are not altered in Thy1-aSyn mice
The core of the oscillatory clock that generates circadian rhythms in the SCN consists of an evolutionarily conserved transcriptional/translational feedback loop that drives rhythmic activity of key clock genes such as Per2 (Hastings et al., 2003), which in turn drive the oscillation of action potentials in SCN neurons that project to other regions of the brain. A normally functioning circadian clock in the SCN would cause SCN Per2 expression levels to be high during daylight and low in
In Thy1-aSyn mice, the firing rate of SCN neurons is reduced early in the progression of PD
SCN neurons are spontaneously active and generate action potentials with peak activity during the day (Colwell, 2011). In the daytime, we found that the excitability of SCN neurons was significantly reduced in the Thy1-aSyn mice (Fig. 3) (Kudo et al., 2011b). At this age (3 months) we did not see evidence of cell loss within the SCN; however, we have not yet looked at older mice. In the Thy1-aSyn model, firing rate is also dramatically reduced in the striatal medium spiny neurons (Wu et al., 2010
The decreased firing rate of SCN neurons in Thy1-aSyn mice may be due to mitochondrial dysfunction and oxidative stress
Although aSyn is primarily thought to be important for synaptic vesicle release and recycling, there is increasing evidence of its colocalization with the mitochondrial membrane (Li et al., 2007, Nakamura et al., 2008). Furthermore, mitochondrial function can be impaired upon mis-expression of aSyn (Martin et al., 2006, Xie and Chung, in press) and conversely, the mitochondrial toxin MPTP leads to aSyn accumulation (Purisai et al., 2005). Other mouse genetic models of PD, also show altered
Future directions
These types of disruptions of the circadian system that are caused by altered coupling within the SCN circuit are likely to have profound consequences on patient health (Bechtold et al., 2010, Hastings et al., 2003, Karatsoreos et al., 2011, Reddy and O'Neill, 2010, Takahashi et al., 2008a). There is mounting evidence that robust circadian rhythms are a necessary component to optimum health. In recent years, a wide range of studies have demonstrated that disruption of the circadian system leads
Acknowledgments
We acknowledge the support and encouragement from our colleagues at UCLA, including Drs. Chesselet and McCracken. We also thank Dr. Nurmi for insightful comments on a draft of the manuscript. Finally, we thank Ms. Donna Crandall for assistance with the graphics.
References (193)
- et al.
Effects of sleep deprivation on impulsive behaviors in men and women
Physiol. Behav.
(2007) Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease
Physiol. Behav.
(2011)- et al.
Sleep deprivation lowers inhibition and enhances impulsivity to negative stimuli
Behav. Brain Res.
(2011) - et al.
Genomics and systems approaches in the mammalian circadian clock
Curr. Opin. Genet. Dev.
(2010) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) - et al.
Sleep disorders in Parkinson's disease: the contribution of the MPTP non-human primate model
Exp. Neurol.
(2009) - et al.
Circadian dysfunction in disease
Trends Pharmacol. Sci.
(2010) Predicting the future in idiopathic rapid-eye movement sleep behaviour disorder
Lancet Neurol.
(2010)- et al.
A dual-hit animal model for age-related parkinsonism
Prog. Neurobiol.
(2010) - et al.
The challenge of non-motor symptoms in Parkinson's disease
Prog. Brain Res.
(2010)
Genetic animal models of Parkinson's disease
Neuron
Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state
Neuroscience
Sleep disorders in Parkinson's disease: many causes, few therapeutic options
J. Neurol. Sci.
Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein
Neuroscience
The MPTP-lesioned non-human primate models of Parkinson's disease. Past, present, and future
Prog. Brain Res.
Circadian oscillation of innate immunity components in mouse small intestine
Mol. Immunol.
Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood
Curr. Biol.
Disorganization of the rat activity rhythm by chronic treatment with methamphetamine
Physiol. Behav.
Activity rhythms in the circadian domain appear in suprachiasmatic nuclei lesioned rats given methamphetamine
Physiol. Behav.
Dopamine receptor-mediated regulation of neuronal “clock” gene expression
Neuroscience
Sleep–wake changes in the premotor stage of Parkinson disease
J. Neurol. Sci.
The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases
Sleep Med. Rev.
Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study
Lancet Neurol.
Multi-organ autonomic dysfunction in Parkinson disease
Parkinsonism Relat. Disord.
Cardiovascular dysautonomia in Parkinson disease: from pathophysiology to pathogenesis
Neurobiol. Dis.
Persistent subthreshold voltage-dependent cation single channels in suprachiasmatic nucleus neurons
Neuroscience
Circadian dysfunction in a mouse model of Parkinson's disease
Exp. Neurol.
Societal costs of insomnia
Sleep Med. Rev.
Excessive daytime sleepiness and subsequent development of Parkinson disease
Neurology
Expanding insights of mitochondrial dysfunction in Parkinson's disease
Nat. Rev. Neurosci.
Nocturnal sleep structure and temperature slope in MPTP treated monkeys
J. Neural Transm.
Circadian proteins and genotoxic stress response
Circ. Res.
REM sleep behavior disorder: motor manifestations and pathophysiology
Mov. Disord.
A neural circuit for circadian regulation of arousal
Nat. Neurosci.
Emotional dysfunction in Parkinson's disease
Behav. Neurol.
Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease
Brain
The staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered
Mov. Disord.
Disruption of the circadian clock within the cardiomyocyte influences myocardial contractile function, metabolism, and gene expression
Am. J. Physiol. Heart Circ. Physiol.
The suprachiasmatic nucleus balances sympathetic and parasympathetic output to peripheral organs through separate preautonomic neurons
J. Comp. Neurol.
Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro
Science
Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein
J. Neurosci.
Dysregulation of inflammatory responses by chronic circadian disruption
J. Immunol.
Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening
Proc. Natl. Acad. Sci. U.S.A.
Sleep and neurodegenerative diseases
Semin. Neurol.
REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century
Neurology
Preventing dehydration during sleep
Nat. Neurosci.
Linking neural activity and molecular oscillations in the SCN
Nat. Rev. Neurosci.
Alpha-Synuclein and neuronal cell death
Mol. Neurodegener.
Toxic role of K + channel oxidation in mammalian brain
J. Neurosci.
Neuropsychiatry and Behavioral Neuroscience
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2018, Sleep MedicineCitation Excerpt :In recognition of the unique problems that these symptoms pose for PD patients, more novel approaches to treatment have diverged from the traditional lines of DA replacement, thereby implicating the involvement of other systems in the etiology and treatment of PD [11,12]. The circadian system is one such system hypothesized to be involved and it is receiving an increasing amount of attention in regard to the secondary symptoms of depression and insomnia commonly expressed in PD patients [13–17]. This approach is based on the compellation of four areas of endeavor intimating circadian system involvement: first, that impaired sleep is circadian driven and contributes to the high morbidity of PD [6,8,18–29]; second, that depression is prevalent in 60% of PD patients and often precedes disease onset for two to three decades prior to diagnosis [6,10,30,31]; third, that RSBD itself proceeds and predicts the onset of PD [9,20,32–35] and fourth, that DA replacement interferes with circadian function [1,36–38].
Emerging preclinical interest concerning the role of circadian function in Parkinson's disease
2018, Brain ResearchCitation Excerpt :They too concluded that DA deficiency weakened circadian output, a phenomenon which is commonly seen in PD. In a subsequent paper reviewing changes in the SCN in the transgenic mouse model (Willison et al., 2013), it was hypothesized that the circadian deficits of PD are attributable to aberrant signalling output from the SCN, which is caused by the pathological mechanisms of PD aetiology, including DA deficiency. The authors went further to suggest that circadian dysfunction may even accelerate the pathology underlying PD and that more aggressive treatment of circadian misalignment and sleep problems early in the disease may help to slow or even prevent disease progression.