Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Circadian rhythm dysfunction: a novel environmental risk factor for Parkinson’s disease


Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder. Although rare genetically linked cases of PD have been reported, most incidences are sporadic in nature. Late-onset, sporadic PD is thought to result from the combined effects of genetic and environmental risk factors exposure. Sleep and circadian rhythm disorders are recurrent among PD patients and appear early in the disease. Although some evidence supports a relationship between circadian disruption (CD) and PD, whether this is secondary to the motor symptoms or, indeed, is a factor that contributes to the pathogenesis of the disease remains to be investigated. In the present paper, we studied the direct consequence of chronic CD on the development of the phenotype in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinen) model of PD. Pre-exposure to CD to mice treated with MPTP resulted in an exacerbation of motor deficit and a significant reduction in the capability of acquiring motor skills. These changes were associated with a greater loss of tyrosine hydroxylase cell content and intense neuroinflammation. Taken together, our findings demonstrate that CD by triggering a robust neuroinflammatory reaction and degeneration of the nigral-dopaminergic neuronal system exacerbates motor deficit. They support the novel hypothesis that circadian rhythm disorder is an environmental risk factor for developing PD.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6


  1. Goedert M, Spillantini MG, Del Tredici K, Braak H . 100 years of Lewy pathology. Nat Rev Neurol 2013; 9: 13–24.

    CAS  Article  Google Scholar 

  2. Wilson RS, Arnold SE, Schneider JA, Kelly JF, Tang Y, Bennet DA . Chronic psychological distress and risk of Alzheimer’s disease in old age. Neuroepidemiology 2006; 27: 143–153.

    Article  Google Scholar 

  3. Comella CL . Sleep disturbances and excessive daytime sleepiness in Parkinson’s disease: an overview. J Neural Transm Suppl 2006; 70: 349–355.

    Google Scholar 

  4. Lima MMS, Andersen ML, Reksidler AB, MABF Vital, Tufik S . The role of the substantia nigra pars compacta in regulating sleep patterns in rats. PLoS ONE 2007; 2: e513.

    Article  Google Scholar 

  5. Chen H, Schernhammer R, Schwarzschild MA, Ascherio A . A prospective study of night shift work, sleep duration, and risk of Parkinson’s disease. Am J Epidemiol 2006; 163: 726–730.

    Article  Google Scholar 

  6. Gao J, Huang X, Park Y, Hollenbeck A, Blair A, Schatzkin et al. Daytime napping: night-time sleeping, and Parkinson’s disease. Am J Epidemiol 2011; 173: 1032–1038.

    Article  Google Scholar 

  7. Abbot RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS et al. Excessive daytime sleepiness and subsequent development of Parkinson’s disease. Neurology 2005; 65: 1442–1446.

    Article  Google Scholar 

  8. Di Meco A, Joshi YB, Praticò D . Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles. Neurobiol Aging 2014; 35: 1813–1820.

    CAS  Article  Google Scholar 

  9. Coppi A, Merali S, Eichinger D . The enteric parasite Entamoeba uses an autocrine catecholamine system during differentiation into the infectious cyst stage. J Biol Chem 2002; 277: 8083–8090.

    CAS  Article  Google Scholar 

  10. Merali S, Clarkson AB . Polyamine analysis using N-hydroxysuccinimidyl-6-aminoquinoyl carbamate for pre-column derivatization. J Chromatogr B Biomed Sci Appl 1996; 675: 321–326.

    CAS  Article  Google Scholar 

  11. Lauretti E, Di Meco A, Chu J, Praticò D . Modulation of AD neuropathology and memory impairments by the isoprostane F2α is mediated by the thromboxane receptor. Neurobiol Aging 2014; 36: 812–820.

    Article  Google Scholar 

  12. Joshi YB, Giannopoulos PF, Chu J, Sperow M, Kirby LG, Abood ME et al. Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy in a mouse model of Alzheimer's disease. Hum Mol Genet 2014; 23: 6894–6902.

    CAS  Article  Google Scholar 

  13. Sedelis M, Hofele K, Auburger GW, Morgan S, Huston JP, Schwarting RK . MPTP susceptibility in the mouse: behavioral, neurochemical, and histological analysis of gender and strain differences. Behav Genet 2000; 30: 171–182.

    CAS  Article  Google Scholar 

  14. Lim MM, Xu J, Holtzman DM, Mach RH . Sleep deprivation differentially affects dopamine receptor subtypes in mouse striatum. Neuroreport 2011; 22: 489–493.

    CAS  Article  Google Scholar 

  15. Willison LD, Kudo T, Loh DH, Kuljis D, Colwell CS . Circadian dysfunction may be a key component of the non-motor symptoms of Parkinson's disease: insights from a transgenic mouse model. Exp Neurol 2013; 243: 57–66.

    Article  Google Scholar 

  16. Campos Costa I, Nogueira Carvalho H, Fernandes L . Aging, circadian rhythms and depressive disorders: a review. Am J. Neurodegener Dis 2013; 2: 228–246.

    Google Scholar 

  17. Castanon-Cervantes O, Wu M, Ehlen JC, Paul K, Gamble KL, Johnson RL et al. Dysregulation of inflammatory responses by chronic circadian disruption. J Immunol 2010; 185: 5796–5805.

    CAS  Article  Google Scholar 

  18. Buxton OM, Marcelli E . Short and long sleep are positively associated with obesity, diabetes, hypertension, and cardiovascular disease among adults in the United States. Soc Sci Med 2010; 71: 1027–1036.

    Article  Google Scholar 

  19. Lima MM, Reksidler AB, Vital MA . The neurobiology of the substantia nigra pars compacta: from motor to sleep regulation. J Neural Transm Suppl 2009; 135–145.

  20. Hood S, Cassidy P, Cossette MP, Weigl Y, Verwey M, Robinson B et al. Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. J Neurosci 2010; 30: 14046–14058.

    CAS  Article  Google Scholar 

  21. Videnovic A, Golombek D . Circadian and sleep disorders in Parkinson's disease. Exp Neurol 2013; 243: 45–56.

    Article  Google Scholar 

  22. Parekh PK, Ozburn AR, McClung CA . Circadian clock genes: effects on dopamine, reward and addiction. Alcohol 2015; 49: 341–349.

    CAS  Article  Google Scholar 

  23. Smeyne RJ . Vernice Jackson-Lewis. The MPTP model of Parkinson's disease. Mol Brain Res 2005; 134: 55–67.

    Google Scholar 

  24. Rappold PM, Tieu K . Astrocytes and therapeutics for Parkinson's disease. Neurotherapeutics 2010; 7: 413–423.

    CAS  Article  Google Scholar 

Download references


This study was supported in part by the Wanda Simone Endowment for Neuroscience (PD). We are grateful to Dr Anna M Gumpert for technical assistance with the Imaging Software NIS Element AR.

Author contributions

EL and DP conceived and designed the study, EL and DP wrote the manuscript, EL, ADM and SM performed the experiments. All authors reviewed and approved the final version of the manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to D Praticò.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lauretti, E., Di Meco, A., Merali, S. et al. Circadian rhythm dysfunction: a novel environmental risk factor for Parkinson’s disease. Mol Psychiatry 22, 280–286 (2017).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links