DOPA pheomelanin is increased in nigral neuromelanin of Parkinson's disease.

Neuromelanin (NM) in dopaminergic neurons of human substantia nigra (SN) has a melanic component that consists of pheomelanin and eumelanin moieties and has been proposed as a key factor contributing to dopaminergic neuron vulnerability in Parkinson's disease (PD). While eumelanin is considered as an antioxidant, pheomelanin and related oxidative stress are associated with compromised drug and metal ion binding and melanoma risk. Using postmortem SN from patients with PD or Alzheimer's disease (AD) and unaffected controls, we identified increased L-3,4-dihydroxyphenylalanine (DOPA) pheomelanin and increased ratios of dopamine (DA) pheomelanin markers to DA in PD SN compared to controls. Eumelanins derived from both DOPA and DA were reduced in PD group. In addition, we report an increase in DOPA pheomelanin relative to DA pheomelanin in PD SN. In AD SN, we observed unaltered melanin markers despite reduced DOPA compared to controls. Furthermore, synthetic DOPA pheomelanin induced neuronal cell death in vitro while synthetic DOPA eumelanin showed no significant effect on cell viability. Our findings provide insights into the different roles of pheomelanin and eumelanin in PD pathophysiology. We anticipate our study will lead to further investigations on pheomelanin and eumelanin individually as biomarkers and possibly therapeutic targets for PD.

Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson's disease.

BACKGROUND: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson's disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. METHODS: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. RESULTS: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. CONCLUSION: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.

Inhibition of PAR-1 delays aging via activating AMPK in C. elegans.

The antagonistic pleiotropy theory of aging suggests that genes essential for growth and development are likely to modulate aging later in life. Previous studies in C. elegans demonstrate that inhibition of certain developmentally essential genes during adulthood leads to significant lifespan extension. PAR-1, a highly conserved serine/threonine kinase, functions as a key cellular polarity regulator during the embryonic development. However, the role of PAR-1 during adulthood remains unknown. Here we show that inhibition of par-1 either by a temperature-sensitive mutant or by RNAi knockdown only during adulthood is sufficient to extend lifespan in C. elegans. Inhibition of par-1 also improves healthspan, as indicated by increased stress resistance, enhanced proteotoxicity resistance, as well as reduced muscular function decline over time. Additionally, tissue-enriched RNAi knockdown analysis reveals that PAR-1 mainly functions in the epidermis to regulate lifespan. Further genetic epistatic and molecular studies demonstrate that the effect of par-1 on lifespan requires the AMP-activated protein kinase (AMPK), and RNAi knockdown of par-1 results in age-dependent AMPK activation and reduced lipid accumulation in the metabolic tissue. Taken together, our findings reveal a previously undescribed function of PAR-1 in adulthood, which will help to understand the molecular links between development and aging.

Shen-Jing as a Chinese Medicine Concept Might Be a Counterpart of Stem Cells in Regenerative Medicine.

As the epitome of the modern regenerative medicine, stem cells were proposed in the basic sense no more than 200 years ago. However, the concept of "stem cells" existed long before the modern medical description. The hypothesis that all things, including our sentient body, were generated from a small origin was shared between Western and Chinese people. The ancient Chinese philosophers considered Jing (also known as essence) as the origin of life. In Chinese medicine (CM), Jing is mainly stored in Kidney (Shen) and the so-called Shen-Jing (Kidney essence). Here, we propose that Shen-Jing is the CM term used to express the meaning of "origin and regeneration". This theoretical discovery has at least two applications. First, the actions underlying causing Shen-Jing deficiency, such as excess sexual intercourse, chronic diseases, and aging, might damage the function of stem cells. Second, a large number of Chinese herbs with Shen-Jing-nourishing efficacy had been proven to affect stem cell proliferation and differentiation. Therefore, if Shen-Jing in CM is equivalent with stem cells in regenerative medicine, higher effective modulators for regulating stem-cell behaviors from Kidney-tonifying herbs would be expected.

Bimolecular Fluorescence Complementation of Alpha-synuclein Demonstrates its Oligomerization with Dopaminergic Phenotype in Mice.

Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of αSyn in mice. Overexpression and oligomerization of αSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of αSyn in PD and to explore therapeutic approaches.

Icariin inhibits LPS-induced cell inflammatory response by promoting GRα nuclear translocation and upregulating GRα expression.

AIMS: Icariin (ICA) is a flavonoid isolated from certain plant species in the genus Epimedium, especially Epimedium brevicornum. Previous studies indicated that ICA has certain regulatory effects on some inflammatory diseases, and that ICA regulates the activity of glucocorticoid receptor (GR) and NF-κB. But the causal link between GR and NF-κB and other downstream pathways in effects of ICA remained elusive, therefore here we have investigated whether ICA could promote GR function, in turn, to regulate NF-κB and/or other factors to achieve its anti-inflammatory effect. MAIN METHODS: Inflammatory cell models were induced by lipopolysaccharide (LPS) in RAW 264.7 and HeLa cell line. Observation of GRα nuclear translocation by confocal laser scanning microscopy. GRα and inflammatory cytokines expression was detected by RT-qPCR, Western Blotting and ELISA. Co-immunoprecipitation technique was used to detect the binding of GRα to downstream transcription factors. GRα activity was blocked by GRα antagonist RU486, and GR downstream transcription factors including NF-κB, c-Jun, and Stat3 were silenced by corresponding RNA interference. KEY FINDINGS: In both inflammatory cell models, ICA decreased LPS-induced production of inflammatory cytokines (IL-6 and TNF-α). While ICA up-regulated the amount of GRα and promoted its nucleus translocation. The increased GRα in the nucleus by ICA bound more NF-κB, c-Jun, and Stat3. Blockade GRα and silence of NF-κB, c-Jun, and Stat3 expression partially abolished the anti-inflammatory effects of ICA. SIGNIFICANCE: Promoted GR function and the consequent inhibition of pro-inflammatory transcription factors contribute a main mechanism by which ICA exerts its anti-inflammatory effect.

Icaritin enhances mESC self-renewal through upregulating core pluripotency transcription factors mediated by ERα.

Utilization of small molecules in modulation of stem cell self-renewal is a promising approach to expand stem cells for regenerative therapy. Here, we identify Icaritin, a phytoestrogen molecule enhances self-renewal of mouse embryonic stem cells (mESCs). Icaritin increases mESCs proliferation while maintains their self-renewal capacity in vitro and pluripotency in vivo. This coincides with upregulation of key pluripotency transcription factors OCT4, NANOG, KLF4 and SOX2. The enhancement of mESCs self-renewal is characterized by increased population in S-phase of cell cycle, elevation of Cylin E and Cyclin-dependent kinase 2 (CDK2) and downregulation of p21, p27 and p57. PCR array screening reveals that caudal-related homeobox 2 (Cdx2) and Rbl2/p130 are remarkably suppressed in mESCs treated with Icaritin. siRNA knockdown of Cdx2 or Rbl2/p130 upregulates the expression of Cyclin E, OCT4 and SOX2, and subsequently increases cell proliferation and colony forming efficiency of mESCs. We then demonstrate that Icaritin co-localizes with estrogen receptor alpha (ERα) and activates its nuclear translocation in mESCs. The promotive effect of Icaritin on cell cycle and pluripotency regulators are eliminated by siRNA knockdown of ERα in mESCs. The results suggest that Icaritin enhances mESCs self-renewal by regulating cell cycle machinery and core pluripotency transcription factors mediated by ERα.

The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.

OBJECTIVE: Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. METHODS: Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. RESULTS: MC1Re/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. INTERPRETATION: Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406.

The associations between Parkinson's disease and cancer: the plot thickens.

Epidemiological studies support a general inverse association between the risk of cancer development and Parkinson's disease (PD). In recent years however, increasing amount of eclectic evidence points to a positive association between PD and cancers through different temporal analyses and ethnic groups. This positive association has been supported by several common genetic mutations in SNCA, PARK2, PARK8, ATM, p53, PTEN, and MC1R resulting in cellular changes such as mitochondrial dysfunction, aberrant protein aggregation, and cell cycle dysregulation. Here, we review the epidemiological and biological advances of the past decade in the association between PD and cancers to offer insight on the recent and sometimes contradictory findings.