Mutations in TARDBP, encoding TAR DNA-binding protein-43 (TDP-43), are associated with TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We compared wild-type TDP-43 and an ALS-associated mutant TDP-43 in vitro and in vivo. The A315T mutant enhances neurotoxicity and the formation of aberrant TDP-43 species, including protease-resistant fragments. The C terminus of TDP-43 shows sequence similarity to prion proteins. Synthetic peptides flanking residue 315 form amyloid fibrils in vitro and cause neuronal death in primary cultures. These data provide evidence for biochemical similarities between TDP-43 and prion proteins, raising the possibility that TDP-43 derivatives may cause spreading of the disease phenotype among neighboring neurons. Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies. © 2011 Nature America, Inc. All rights reserved.

Guo Weirui;Chen Yanbo;Zhou Xiaohong;Yang Mengxue;Ye Haihong;Zhu Li;Liu Jianghong;Wu Jane Y.;Kar Amar;Ray Payal;Chen Xiaoping;Zhang David;Fushimi Kazuo;Shen Yan;Xu Qi;Rao Elizabeth J.;Xu Meng;Yang Yanlian;Wang Chen;Bigio Eileen H.;Mesulam Marsel

Nature Structural and Molecular Biology

2011

The nervous system is one of the most complicated organ systems in invertebrates and vertebrates. Down syndrome cell adhesion molecule (DSCAM) of the immunoglobulin (Ig) superfamily is expressed widely in the nervous system during embryonic development. Previous studies in Drosophila suggest that Dscam plays important roles in neural development including axon branching, dendritic tiling and cell spacing. However, the function of the mammalian DSCAM gene in the formation of the nervous system remains unclear. Here, we show that Dscam ^del17 mutant mice exhibit severe hydrocephalus, decreased motor function and impaired motor learning ability. Our data indicate that the mammalian DSCAM gene is critical for the formation of the central nervous system. © 2011 Higher Education Press and Springer-Verlag Berlin Heidelberg.

Xu Yiliang;Shen Yan;Xu Qi;Ye Haihong;Zhu Li;Liu Jianghong;Wu Jane Y.

Protein and Cell

2011

Mutations in the Fused in sarcoma/Translated in liposarcoma gene (FUS/TLS, FUS) have been identified among patients with amyotrophic lateral sclerosis (ALS). FUS protein aggregation is a major pathological hallmark of FUS proteinopathy, a group of neurodegenerative diseases characterized by FUS-immunoreactive inclusion bodies. We prepared transgenic Drosophila expressing either the wild type (Wt) or ALS-mutant human FUS protein (hFUS) using the UAS-Gal4 system. When expressing Wt, R524S or P525L mutant FUS in photoreceptors, mushroom bodies (MBs) or motor neurons (MNs), transgenic flies show age-dependent progressive neural damages, including axonal loss in MB neurons, morphological changes and functional impairment in MNs. The transgenic flies expressing the hFUS gene recapitulate key features of FUS proteinopathy, representing the first stable animal model for this group of devastating diseases. © 2011 Higher Education Press and Springer-Verlag Berlin Heidelberg.

Chen Yanbo;Shen Yan;Xu Qi;Yang Mengxue;Deng Jianwen;Ye Ye;Zhu Li;Liu Jianghong;Ye Haihong;Li Yan;Wu Jane Y.;Chen Xiaoping;Rao Elizabeth J.;Fushimi Kazuo;Zhou Xiaohong;Bigio Eileen H.;Mesulam Marsel

Protein and Cell

2011

The dopamine transporter (DAT1) gene has been implicated in the pathogenesis of many neuropsychiatric disorders, including schizophrenia. The present study aimed to investigate association of the DAT1 gene polymorphisms with schizophrenia in a Han Chinese population. Two single nucleotide polymorphisms (SNPs) in the DAT1 gene (rs2975223 and rs2455391) were tested in 368 patients with schizophrenia and 420 healthy controls, of whom 293 patients underwent an assessment of psychotic symptoms through the positive and negative syndrome scale (PANSS). The chi-square test (χ ² ) showed disease association for rs2455391 (corrected p=0.023 for allelic association and p=0.034 for genotypic association, respectively). The rs2975223(G)-rs2455391(C) haplotype was associated with increased risk of the illness (p=0.0012, OR=2.09, 95% CI=1.28-3.42). Quantitative trait analysis showed that rs2455391 was associated with positive symptoms, general symptoms and global symptoms but not with negative symptoms. The present results suggest that the DAT1 gene may be mainly involved in the development of the positive symptoms in the Chinese population. © 2012 Elsevier Ireland Ltd.

Zheng Chunming;Shen Yan;Xu Qi

Neuroscience Letters

2012

Objective: To investigate the clinical, electroencephalogram (EEG) and genetic features of nocturnal frontal lobe epilepsy (NFLE) in the Chinese population. Methods: Clinical examination, EEG recording, mutation screenings in transmembrane domains 1-3 of neuronal nicotinic acetylcholine receptor (nAChR) α4 (CHRNA4), β2 (CHRNB2) and α2 (CHRNA2) using PCR amplification and sequencing were carried out on 6 patients and some members in 3 families with NFLE. Results: Among 6 patients (5 male) with NFLE, the mean age was (20.5 ± 11.5) years and the mean age at onset was (7.3 ± 5.5) years. Clinical features included seizures of dystonic posturing in 2 patients and seizures of hyperkinetic movements in 4 patients with the maximum frequency of 6 seizures within one night. The ictal and interictal video-EEG (VEEG) of frontal lobes showed epileptic discharges, slow wave activity, normal activity or electrode artifacts. There weren't abnormity in other clinical examination and neuroimagings. No mutations were identified in the genes screened. Conclusion: NFLE is a heterogenetic epilepsy syndrome. © 2009 by the Chinese Medical Association.

Chen Yan;Wu Li-Wen;Wang Meng-Yang;Fang Yue;Xu Qi;Shen Yan

Chinese Journal of Neurology

2009

The dopamine receptor genes have been implicated in the pathogenesis of schizophrenia, but definitive evidence of association is still lacking. To identify whether functional variants of the D2-like receptors (DRD2, DRD3 and DRD4) confer risk of schizophrenia, we conducted a two-stage association study. We firstly examined the SNPs in functional genomic regions, such as mRNA splicing, protein coding and the promoter regions in DRD2, DRD3 and DRD4, respectively, for association in 289 Han Chinese cases with schizophrenia and 367 healthy controls and then further analyzed the significantly associated single nucleotide polymorphisms (SNPs) with this disorder in an additional Han Chinese sample consisted of 1351 cases and 1640 control subjects. In the first stage, the chi-square test (χ ² ) showed disease association for rs1076560 in DRD2 (p=0.040 for allelic association and p=0.033 for genotypic association, respectively). However, rs6280 in DRD3 and rs3758653 in DRD4 failed to show either allelic or genotypic association with the illness. The association between rs1076560 and schizophrenia was replicated in the second stage. The rs1076560-T allele, which shifts splicing from the D2 short isoform (D2S) to the D2 long isoform (D2L), was over-presented in the patient group (44%) than in the control group (41%) (χ ² =5.19, p=0.023, OR=1.13, 95% CI=1.02-1.25). Therefore, the rs1076560 variant of DRD2 reliably influences risk of schizophrenia in Han Chinese, although more data are required to elucidate the pathophysiological mechanisms of possessing this risk-conferring variant. © 2012 Elsevier Ireland Ltd.

Zheng Chunming;Shen Yan;Xu Qi

Neuroscience Letters

2012

Objective: To determine the spatio-temporal expression of p70S6k activation in hippocampus in mesial temporal lobe epilepsy. Methods: Temporal lobe epilepsy model was established by stereotaxically unilateral and intrahip-pocampal injection of kainite acid (KA) in adult male C57BL/6 mice. Latent and chronic epileptogenesis were represented by mice 5 days after KA injection (n=5) and mice 5 weeks after KA injection (n=8), respectively. Control mice (n=5) were injected with saline. Immunohistochemical assays were performed on brain sections of the mice. Results: Hippocampus both ipsilateral and contralateral to the KA injection displayed significantly up-regulated pS6 immunoreactivity in dispersed granule cells in 5-day and 5-week model mice. Conclusion: The activation of p70S6k is mainly located in the dentate gyrus in KA-induced mouse model of temporal lobe epilepsy, indicating that the activation may be related with the disperse degree and hypertrophy of granule cells. © 2012 Chinese Academy Medical Sciences.

Xing Xiao-Liang;Sha Long-Ze;Shen Yan;Xu Qi;Yao Yuan;Wu Li-Wen

Chinese Medical Sciences Journal

2012

This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E-35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males. © 2011 Springer-Verlag.

Chen Yanbo;Zhang Jiexu;Shen Yan;Xu Qi;Zhang Li

Human Genetics

2012

Objective: To explore the role of β-catenin in the pathogenesis of mesial temporal lobe epilepsy. Methods: Kainic acid-induced rat models of medial temporal lobe epilepsy was established. The expression of β-catenin in the normal mice and the model mice were detected using Western blot analysis. The expression of β-catenin at human hippocampus was detected using immunohistochemical analysis and immunofluorescence and compared between patients with non-hippocampal sclerosis temporal lobe epilepsy and those with hippocampal sclerosis epilepsy. Results: The pathologies of model mice were similar with those in mice with hippcampal sclerosis temporal lobe epilepsy, demonstrating that the mice model was successfully established. Western blot analysis showed no significant difference of β-catenin expression between normal mice and model mice. As shown by immunohistochemical analysis and immunofluorescence, β-catenin expression in human hippocampus was also not significantly different between patients with temporal lobe epilepsy without hippocampal sclerosis and those with hippcampal sclerosis. Conclusion: β-catenin may not be involved in the development of hippocampal sclerosis of mesial temporal lobe epilepsy.

Xing Xiao-Liang;Sha Long-Ze;Shen Yan;Xu Qi;Zhang Dan;Wu Li-Wen

Acta Academiae Medicinae Sinicae

2011

Objective: The precise mechanism of major depressive disorder (MDD) is poorly understood. On the basis of the neurotrophin hypothesis, initial findings from our previous studies, and the functions of epidermal growth factor (EGF) in the central nervous system, we proposed that EGF might contribute to the development of MDD, which was investigated in this study. Methods: Eight single nucleotide polymorphisms (SNPs) within the EGF gene were genotyped in 463 patients with MDD and 413 control participants among a Chinese population; of these, the plasma EGF levels of 210 patients and 223 controls were determined using the enzyme-linked immunosorbent assay. To determine the effect of functional SNPs on EGF secretion in HEK293 cells, EGF levels in the supernatants of cultured cells were also assessed. Results: None of the informative SNPs showed an allelic association with MDD, but the cis-phase interaction between rs11569017 and rs11569126 was strongly associated with the illness (P=0.0027). The EGF levels in plasma were significantly lower in the patient group than in the control group (P<0.0001). The EGF levels were also significantly lower in patients with the rs11569017-TT genotype than those with either the AA genotype (P=0.013) or the AT genotype (P=0.004); the rs11569017 minor allele significantly affected the expression of the EGF gene (P=0.0004). Conclusion: The cis-phase interaction between the SNPs within the EGF locus may contribute toward the etiology of MDD. The plasma EGF levels may be a useful biomarker for the early diagnosis, treatment, and prognosis of major psychiatric disorders. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Tian Wenmin;Zhang Juan;Shen Yan;Xu Qi;Zhang Kerang;Yang Hong;Sun Yan

Psychiatric Genetics

2012