Melatonin attenuates hLRRK2-induced sleep disturbances and synaptic dysfunction in a Drosophila model of Parkinson's disease

Sun,Xicui; Ran,Dongzhi; Zhao,Xiaofeng; Huang,Yi; Long,Simei; Liang,Fengyin; Guo,Wenyuan; Nucifora,Frederick  C.; Gu,Huaiyu; Lu,Xilin; Chen,Ling; Zeng,Jinsheng; Ross,Christopher  A.; Pei,Zhong

doi:10.3892/mmr.2016.4991

Melatonin attenuates hLRRK2-induced sleep disturbances and synaptic dysfunction in a Drosophila model of Parkinson's disease

Authors:
- Xicui Sun
- Dongzhi Ran
- Xiaofeng Zhao
- Yi Huang
- Simei Long
- Fengyin Liang
- Wenyuan Guo
- Frederick C. Nucifora
- Huaiyu Gu
- Xilin Lu
- Ling Chen
- Jinsheng Zeng
- Christopher A. Ross
- Zhong Pei
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Affiliations: Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Key Laboratory, Liaocheng Hospital, Liaocheng, Shandong 252000, P.R. China, Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Published online on: March 16, 2016 https://doi.org/10.3892/mmr.2016.4991
Pages: 3936-3944

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Abstract

Sleep problems are the most common non-motor symptoms in Parkinson's disease (PD), and are more difficult to treat than the motor symptoms. In the current study, the role of human leucine-rich repeat kinase 2 (hLRRK2), the most common genetic cause of PD, was investigated with regards to sleep problems, and the therapeutic potential of melatonin in hLRRK2‑associated sleep problems was explored in Drosophila. hLRRK2 was selectively expressed in the mushroom bodies (MBs) in Drosophila and sleep patterns were measured using the Drosophila Activity Monitoring System. MB expression of hLRRK2 resulted in sleep problems, presynaptic dysfunction as evidenced by reduced miniature excitatory postsynaptic current (mEPSC) and excitatory postsynaptic potential (EPSP) frequency, and excessive synaptic plasticity such as increased axon bouton density. Treatment with melatonin at 4 mM significantly attenuated the sleep problems and rescued the reduction in mEPSC and EPSP frequency in the hLRRK2 transgenic flies. The present study demonstrates that MB expression of hLRRK2 in flies recapitulates the clinical features of the sleep disturbances in PD, and that melatonin attenuates hLRRK2-induced sleep disorders and synaptic dysfunction, suggesting the therapeutic potential of melatonin in PD patients carrying LRRK2 mutations.

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