Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by movement dysfunction due to selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. Non-motor symptoms of PD (e.g., sensory dysfunction, sleep disturbance, constipation, neuropsychiatric symptoms) precede motor symptoms, appear at all stages, and impact the quality of life, but they frequently go unrecognized and remain untreated. Even when identified, traditional dopamine replacement therapies have little effect. We discuss here the pathology of two PD-associated non-motor symptoms: olfactory dysfunction and depression. Olfactory dysfunction is one of the earliest non-motor symptoms in PD and predates the onset of motor symptoms. It is accompanied by early deposition of Lewy pathology and neurotransmitter alterations. Because of the correlation between olfactory dysfunction and an increased risk of progression to PD, olfactory testing can potentially be a specific diagnostic marker of PD in the prodromal stage. Depression is a prevalent PD-associated symptom and is often associated with reduced quality of life. Although the pathophysiology of depression in PD is unclear, studies suggest a causal relationship with abnormal neurotransmission and abnormal adult neurogenesis. Here, we summarize recent progress in the pathology of the non-motor symptoms of PD, aiming to provide better guidance for its effective management.

Mutations in theleucine-rich repeat kinase 2(LRRK2) gene are the most common genetic cause of Parkinson's disease (PD). The neuropathology ofLRRK2mutation-related PD, including increased dopaminergic neurodegeneration and Lewy bodies, is indistinguishable from that of idiopathic PD. The subtle nonmotor phenotypes ofLRRK2mutation-related PD have not been fully evaluated. In the present study, we examined anxiety/depression-like behaviors and accompanying neurochemical changes in differently aged transgenic (Tg) mice expressing human mutant LRRK2 G2019S. Through multiple behavioral tests, including light–dark test, elevated plus maze, sucrose preference test, forced swimming test, and tail-suspension test, we found that anxiety/depression-like behavior appeared in middle-aged (43–52 weeks) Tg mice before the onset of PD-like motor dysfunction. These behavioral tests were performed using both male and female mice, and there were no sex-related differences in behavioral changes in the middle-aged Tg mice. Along with behavioral changes, serotonin levels also significantly declined in the hippocampus of Tg mice. Additionally, increases in the expression of the 5-HT_1Areceptor (5-HT_1AR) grew more significant with aging and were detected in the hippocampus, amygdala, and dorsal raphe nucleus.In vitrostudy using the serotonergic RN46A and hippocampal HT22 cells showed that 5-HT_1AR upregulation was related to enhanced expression of LRRK2 G2019S and was attenuated by the LRRK2 inhibitor LRRK2-IN-1. Wild-type LRRK2 had no significant effect on 5-HT_1AR transcription. The present study provides the firstin vivoandin vitroevidence demonstrating abnormal regulation of 5-HT_1AR along with the manifestation of anxiety/depression-like, nonmotor symptom in PD related to LRRK2.SIGNIFICANCE STATEMENTParkinson's disease (PD), the second most common neurodegenerative disorder, is clinically characterized by motor dysfunctions. In most cases, various nonmotor symptoms present several years before the onset of the classical motor features of PD and severely affect the quality of life of patients. Here, we demonstrate the causative role ofleucine-rich repeat kinase 2(LRRK2), a common PD-linked mutation, in the development of anxiety/depression-like behaviors. We found that age-dependent 5-HT_1Areceptor upregulation in the hippocampus, amygdala, and dorsal raphe nucleus is accompanied by the expression of theLRRK2mutant phenotype. Our findings demonstrating a potential mechanism for nonmotor psychiatric symptoms produced byLRRK2mutation suggest that directly targeting the 5-HT_1Areceptor can improve the therapeutic efficacy of drugs for PD-associated depression.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator for the protection of cells against oxidative and xenobiotic stresses. Recent studies have demonstrated that high constitutive expression of Nrf2 is observed in many types of cancer cells showing resistance to anti-cancer drugs, suggesting that the suppression of overexpressed Nrf2 could be an attractive therapeutic strategy to overcome cancer drug resistance. In the present study, we aimed to find small molecule compounds that enhance the sensitivity of tumor cells to cisplatin induced cytotoxicity by suppressing Nrf2-mediated defense mechanism. A549 lung cancer cells were shown to be more resistant to the anti-cancer drug cisplatin than HEK293 cells, with higher Nrf2 signaling activity; constitutively high amounts of Nrf2-downstream target proteins were observed in A549 cells. Among the three chalcone derivatives 4-methoxy-chalcone (4-MC), hesperidin methylchalcone, and neohesperidin dihydrochalcone, 4-MC was found to suppress transcriptional activity of Nrf2 in A549 cells but to activate it in HEK293 cells. 4-MC was also shown to down-regulate expression of Nrf2 and the downstream phase II detoxifying enzyme NQO1 in A549 cells. The PI3K/Akt pathway was found to be involved in the 4-MC-induced inhibition of Nrf2/ARE activity in A549 cells. This inhibition of Nrf2 signaling results in the accelerated generation of reactive oxygen species and exacerbation of cytotoxicity in cisplatin-treated A549 cells. Taken together, these results suggest that the small molecule compound 4-MC could be used to enhance the sensitivity of tumor cells to the therapeutic effect of cisplatin through the regulation of Nrf2/ARE signaling.