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Zhang L.,Capital Medical University | Ding H.,Capital Medical University | Ding H.,Key Laboratory for Neurodegenerative Diseases of Ministry of Education | Wang D.-H.,Capital Medical University | And 12 more authors.
PLoS ONE | Year: 2013

Recent studies point to an association between the late-onset sporadic Parkinson's disease (PD) and single nucleotide polymorphisms (SNPs) rs1559085 and rs27852 in Ca2+-dependent protease calpain inhibitor calpastatin (CAST) gene. This finding is of interest since loss of CAST activity could result in over activated calpain, potentially leading to Ca2+ dysregulation and loss of substantia nigra neurons in PD. We explored the association between CAST SNPs and late-onset sporadic PD in the Han Chinese population. The study included 615 evaluable patients (363 male, 252 female) with PD and 636 neurologically healthy controls (380 male, 256 female) matched for age, gender, ethnicity, and area of residence. PD cases were identified from the PD cohort of the Chinese National Consortium on Neurodegenerative Diseases (www.chinapd.cn). A total of 24 tag-SNPs were genotyped capturing 95% of the genetic variation across the CAST gene. There was no association found between any of the polymorphisms and PD in all models tested (co-dominant, dominant-effect and recessive-effect). Similarly, none of the common haplotypes was associated with a risk for PD. Our data do not support a significant association between the CAST gene polymorphisms and late onset sporadic PD in the Han Chinese population. © 2013 Zhang et al.


Zhang L.,Capital Medical University | Zhang L.,Key Laboratory for Neurodegenerative Diseases of Ministry of Education | Lin Q.-L.,Capital Medical University | Lin Q.-L.,Key Laboratory for Neurodegenerative Diseases of Ministry of Education | And 17 more authors.
European Review for Medical and Pharmacological Sciences | Year: 2013

BACKGROUND: Circadian rhythms tend to change as animals age; however, the molecular mechanisms underlying these are not yet fully understood. OBJECTIVE: To investigate whether the DNA methylation of clock genes changes with age and contributes to circadian dysfunction in aged animals. METHODS: We examined the methylation of clock promoters in the stomach, kidney, striatum, and spleen by using a methylation-specific polymerase chain reaction (MSP) assay. RESULTS: Our results show that different tissues exhibit specific patterns of clock methylation. Additionally, methylation frequency decreased significantly in older mice at the Per1 promoter in the stomach, but it was significantly increased in older mice at the Cry1, Bmal2, and Npas2 promoters in the spleen. CONCLUSION: The findings from our study suggest that DNA methylation contribute to agerelated changes in circadian rhythms in certain slave oscillators.


Zhang L.,Capital Medical University | Zhang L.,Key Laboratory for Neurodegenerative Diseases of Ministry of Education | Lin Q.,Capital Medical University | Lin Q.,Beijing Geriatric Medical Research Center | And 9 more authors.
Biological Rhythm Research | Year: 2012

DNA methylation plays an important role in the regulation of the expression of clock genes during normal development and in the development of cancer. The methylation status of clock genes may also be associated with aging. However, it is unknown whether promoter methylation is also a regulator for the age-related change of clock expression in human total lymphocytes. In the present study, methylation-specific polymerase chain reaction assays were used to examine the methylation status of seven key clock promoters, namely Bmal1, Clock, Npas2, Per1, Per2, Cry1 and Cry2. The methylation status was examined in 298 healthy subjects categorised into three groups according to their age. Noticeable methylation was only detected in the Cry1 and Npas2 promoters, suggesting their epigenetic regulation may be involved in modulating the expression of clock genes and circadian rhythms in leukocytes. However, their methylation frequency did not differ with age or gender. © 2012 Copyright Taylor and Francis Group, LLC.


Zhang L.,Capital Medical University | Zhang L.,Beijing Engineering Research Center for Nerve System Drugs | Zhang L.,Beijing Institute for Brain Disorders | Zhang L.,Key Laboratory for Neurodegenerative Diseases of Ministry of Education | And 20 more authors.
Age | Year: 2015

The objectives of this study are to investigate the effects of icariin (a main component extracted from Epimedium) on over-expression of α-synuclein and to explore the underlying mechanisms. APPV717I transgenic (Tg) mice and A53T α-synuclein-transfected PC12 cells were used in this study. The content of α-synuclein mRNA was determined by reverse-transcription PCR (RT-PCR). Western blotting and immunohistochemistry were used to detect the protein expression of α-synuclein, parkin, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and heat shock protein 70 (HSP70). In 10-month-old APP Tg mice, α-synuclein expression was increased, and the expression of Parkin, UCH-L1, and HSP70 was decreased in the hippocampus. Intragastrical administration of icariin (30 and 100 μmol/kg) for 6 months (from 4 to 10 months old) decreased α-synuclein expression and increased the expression of Parkin, UCH-L1, and HSP70 in the hippocampus of APP Tg mice. Incubation of icariin (40 and 80 μM) with A53T α-synuclein-transfected PC12 cells for 24 h showed no difference in the expressions of α-synuclein mRNA among model group and icariin-treated groups, but decreased α-synuclein protein expression in both monomer and tetramer. Along with the downregulation of α-synuclein, icariin (40 and 80 μM) elevated the expression of Parkin, UCH-L1, and HSP70 in A53T α-synuclein-transfected cells. Icariin inhibited the over-expression of α-synuclein both in vivo and in vitro. The mechanism of icariin may be related to upregulate Parkin and UCH-L1 expression in ubiquitin-proteasome system and HSP70 in molecular chaperone, thus enhancing the degradation of α-synuclein. It is suggested that icariin may have the potential to treat Alzheimer’s disease (AD) and other synucleinopathies. © 2015, American Aging Association.

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