Parkinson Disease: Chen J

Vosler PS, Brennan CS, Chen J. · Department of Neurology, University of Pittsburgh School of Medicine, S-507, Biomedical Science Tower, Pittsburgh, PA 15213, USA. · Mol Neurobiol. · Pubmed #18686046 No free full text.

Abstract: Calpain is a ubiquitous calcium-sensitive protease that is essential for normal physiologic neuronal function. However, alterations in calcium homeostasis lead to persistent, pathologic activation of calpain in a number of neurodegenerative diseases. Pathologic activation of calpain results in the cleavage of a number of neuronal substrates that negatively affect neuronal structure and function, leading to inhibition of essential neuronal survival mechanisms. In this review, we examine the mechanistic underpinnings of calcium dysregulation resulting in calpain activation in the acute neurodegenerative diseases such as cerebral ischemia and in the chronic neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, prion-related encephalopathy, and amylotrophic lateral sclerosis. The premise of this paper is that analysis of the signaling and transcriptional consequences of calpain-mediated cleavage of its various substrates for any neurodegenerative disease can be extrapolated to all of the neurodegenerative diseases vulnerable to calcium dysregulation.

Ohm OJ, Hoff PI, Aasen LM, Solheim E, Schuster P, Off MK, Chen J. · Institutt for indremedisin, Universitetet i Bergen. · Tidsskr Nor Laegeforen. · Pubmed #19219094 links to  free full text

Abstract: BACKGROUND: Catheter ablation has been increasingly applied in children and adolescents with tachyarrhythmias. The aim of this article is to assess the results of ablation therapy of tachycardias in patients below 18 years of age at Haukeland University Hospital. MATERIAL AND METHODS: 141 patients (70 boys and 71 girls, aged 5-17 (13.5 +/- 3.5 ) years with tachyarrhythmias underwent an electrophysiologic study and catheter ablation in the period 1992-2007. RESULTS: Ablation was successfully performed in 138/141 (98%) patients., The procedure was repeated (3 patients twice) until the arrhythmia substrate disappeared in 16 of 138 patients. 81/141 (57%) patients had accessory pathways; 52 (37%) had double atrioventricular nodal pathways, 48 had concealed and 33 patients had overt (classical Wolff-Parkinson-White-syndrome) atrioventricular pathways. 8 (6%) patients had other atrial or ventricular tachyarrhythmias and 4 (3%) had organic heart disease. Use of a 3D mapping system was decisive for success for ablation in patients with complex cardiac diseases. Procedure-related complications were observed in 2/141 (1.4%) patients of whom one had a temporary third degree and one had a permanent first-degree atrioventricular block which did not entail further treatment. CONCLUSION: Catheter ablation of tachycardia in children and adolescents is a safe treatment method with a high success rate and few complications and should be preferred before drug therapy.

Jao CC, Hegde BG, Chen J, Haworth IS, Langen R. · Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. · Proc Natl Acad Sci U S A. · Pubmed #19066219 links to  free full text

Abstract: alpha-Synuclein is known to play a causative role in Parkinson disease. Although its physiological functions are not fully understood, alpha-synuclein has been shown to interact with synaptic vesicles and modulate neurotransmitter release. However, the structure of its physiologically relevant membrane-bound state remains unknown. Here we developed a site-directed spin labeling and EPR-based approach for determining the structure of alpha-synuclein bound to a lipid bilayer. Continuous-wave EPR was used to assign local secondary structure and to determine the membrane immersion depth of lipid-exposed residues, whereas pulsed EPR was used to map long-range distances. The structure of alpha-synuclein was built and refined by using simulated annealing molecular dynamics restrained by the immersion depths and distances. We found that alpha-synuclein forms an extended, curved alpha-helical structure that is over 90 aa in length. The monomeric helix has a superhelical twist similar to that of right-handed coiled-coils which, like alpha-synuclein, contain 11-aa repeats, but which are soluble, oligomeric proteins (rmsd = 0.82 A). The alpha-synuclein helix extends parallel to the curved membrane in a manner that allows conserved Lys and Glu residues to interact with the zwitterionic headgroups, while uncharged residues penetrate into the acyl chain region. This structural arrangement is significantly different from that of alpha-synuclein in the presence of the commonly used membrane-mimetic detergent SDS, which induces the formation of two antiparallel helices. Our structural analysis emphasizes the importance of studying membrane protein structure in a bilayer environment.

Ding H, Wang F, Ding X, Song X, Lu X, Zhang K, Xiao H, Ye M, Chen J, Zhang Q. · Department of Neurology, the First Affiliated Hospital of Nanjing Medical University, No. 300, Guangzhou Street, Nanjing, Jiangsu Province 210029, P.R. China. · Brain Res. · Pubmed #18950607 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder with genetic risk factors. Semaphorin 5A (SEMA5A) was recognized as a risk factor for PD through high resolution whole genome association study by Maraganore et al. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to check two single nucleotide polymorphisms (SNPs) within SEMA5A in 340 PD patients and 222 PD free cases of Chinese Han ancestry and tested by gene sequencing. We found that the SEMA5A variant genotype (allele) of rs7702187 and rs3798097 had no association with the risk of PD in our sample. The AC haplotype was associated with a significant increased risk of PD and the AT haplotype showed an associated decreased risk of PD compared with the most common haplotype TC. Our findings suggested that haplotypes of SEMA5A may be involved in PD risk in the Chinese Han population.

Weng Z, Signore AP, Gao Y, Wang S, Zhang F, Hastings T, Yin XM, Chen J. · Department of Neurology, and Pittsburgh Institute of Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. · J Biol Chem. · Pubmed #17895242 links to  free full text

Abstract: The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.

Chen M, Margittai M, Chen J, Langen R. · Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA. · J Biol Chem. · Pubmed #17573347 links to  free full text

Abstract: The misfolding and fibril formation of alpha-synuclein plays an important role in neurodegenerative diseases such as Parkinson disease. Here we used electron paramagnetic resonance spectroscopy, together with site-directed spin labeling, to investigate the structural features of alpha-synuclein fibrils. We generated fibrils from a total of 83 different spin-labeled derivatives and observed single-line, exchange-narrowed EPR spectra for the majority of all sites located within the core region of alpha-synuclein fibrils. Such exchange narrowing requires the orbital overlap between multiple spin labels in close contact. The core region of alpha-synuclein fibrils must therefore be arranged in a parallel, in-register structure wherein same residues from different molecules are stacked on top of each other. This parallel, in-register core region extends from residue 36 to residue 98 and is tightly packed. Only a few sites within the core region, such as residues 62-67 located at the beginning of the NAC region, as well as the N- and C-terminal regions outside the core region, are significantly less ordered. Together with the accessibility measurements that suggest the location of potential beta-sheet regions within the fibril, the data provide significant structural constraints for generating three-dimensional models. Furthermore, the data support the emerging view that parallel, in-register structure is a common feature shared by a number of naturally occurring amyloid fibrils.

Zhang H, Ma L, Wang F, Chen J, Zhen X. · Hubei Provincial Key Laboratory for Neural Diseases, Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · Neuropharmacology. · Pubmed #17553535 No free full text.

Abstract: SKF83959, a recently identified selective agonist of putative phosphoinositide-linked (PI-linked) D(1) dopamine (DA) receptor, is found to elicit excellent anti-parkinsonism effects in monkeys and rodents. In the present study, the effects of SKF83959 on L-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) were assessed in a unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). The results indicated that chronic L-DOPA (6 mg/kg) induced a progressive dyskinesia-like behavior in PD rats, whereas SKF83959 (0.5 mg/kg) elicited significantly less severe dyskinesia while exerts its anti-parkinsonian action effectively. Application of D(1) receptor, but not D(2), alpha or 5-HT receptor antagonist attenuated SKF83959-induced dyskinesia, indicating that a D(1) receptor-mediated events, assumed via PI-linked D(1) receptor. Interestingly, chronic co-administration of SKF83959 significantly reduced LID at no expanse of reduction in the anti-parkinsonian potency in PD rats. However, this anti-dyskinesia effect was not observed while SKF83959 was acutely administered in rats with established LID. This implies that chronic SKF83959 attenuated the development of dyskinesia. Immediate early gene FosB is previously reported to positively associate with dyskinesia. However, we found that the anti-dyskinesia effect of chronic SKF83959 was independent of FosB since SKF83959 produced stronger FosB expression in the lesioned striatum than that of L-DOPA while exerting its anti-dyskinesia action. The present data demonstrated that SKF83959 reduces LID by attenuating the development of dyskinesia; the underlying signaling pathway for the anti-dyskinesia action of SKF83959 appears not to depend on FosB.

Kang X, Chen J, Xu Z, Li H, Wang B. · Research Center of Traditional Chinese Medicine, Laboratory of Integrated Traditional Chinese Medicine and Western Medicine on Elderly Encephalopathy, Xijing Hospital, PR China. · Toxicol In Vitro. · Pubmed #17509817 No free full text.

Abstract: Previous studies have suggested that Ginkgo biloba extract (EGb761) has a protective potentiality against apoptosis of neurons or neuron-like cells induced by MPTP. In this study, the effects of EGb761 on PC12 cells injured by paraquat (PQ), a neurotoxin, were tested. The results showed that after incubation of PC12 cells with EGb761 prior to PQ exposure, the PQ-induced decrease of cell viability was significantly reversed, the collapse of mitochondrial membrane potential (MMP) was attenuated and the percentage of apoptotic cells was reduced. Moreover, EGb761 pretreatment evidently increased the numbers of tyrosine hydroxylase (TH) positive and bcl-2 positive cells and degraded the number of caspase-3 positive cells in PQ-injured PC12 cells, in comparison to the treatment with PQ alone. This study indicates that EGb761 has a neuroprotective effect on paraquat-induced apoptosis of PC12 cells. The mechanism underlying the protective effects of EGb761 in PQ-injured PC12 cells might be related to the increase of bcl-2 activation, maintenance of MMP stability and decrease of caspase-3 activation through mitochondria-dependent pathway. The results from this study provide an experimental basis for the potential use of EGb761 in treatment of Parkinson's disease.

Jiang XM, Huang Y, Li DJ, Tang AW, Wang SX, Zhuo Y, Li QS, Chen J, Gao YP. · College of TCM, Southern Medical University, Guangzhou 510515, China. · Zhongguo Zhen Jiu. · Pubmed #16813186 No free full text.

Abstract: OBJECTIVE: To probe the mechanism of electro-scalp acupuncture in treatment of Parkinson's disease (PD) by single photon emission computer tomography (SPECT). METHODS: Five cases of PD received electro-scalp acupuncture at Dingnie Qianxiexian (MS 6), Epangxian III (MS 4), Dingpangxian I (MS 8), Dingpangxian II (MS 9) and Zhenxia Pangxian (MS 14). Contralateral points were selected for pathologic change on one side and bilateral points were selected for pathologic lesion on both sides. All the patients received 99mTc-TRODAT-1 SPECT examination before and after acupuncture treatment of 6 weeks. And activities of dopamine transporter (DAT) were analyzed by the ratio of striatum/occipital lobe (ST/OC), which was evaluated by means of technique of regional of interesting (ROI). RESULTS: The ratio of ST/OC on the same side of the affected extremity before and after treatment were 1.19 +/- 0.15 and 1.24 +/- 0.31 respectively. And on the other side were 0.90 +/- 0.12 and 0.95 +/- 0.25 respectively. They were increased after treatment (P > 0.05). CONCLUSION: Electro-scalp acupuncture can decrease the loss of DAT and improve the activities of DAT in the striatum of the patient of PD.

Chen J, Tang XQ, Zhi JL, Cui Y, Yu HM, Tang EH, Sun SN, Feng JQ, Chen PX. · Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, 510080, P R China. · Apoptosis. · Pubmed #16547587 No free full text.

Abstract: The aim of present study is to explore the cytoprotection of curcumin against 1-methyl-4-phenylpridinium ions (MPP(+))-induced apoptosis and the molecular mechanisms underlying in PC12 cells. Our findings indicated that MPP(+) significantly reduced the cell viability and induced apoptosis of PC12 cells. Curcumin protected PC12 cells against MPP(+)-induced cytotoxicity and apoptosis not only by inducing overexpression of Bcl-2, but also reducing the loss of mitochondrial membrane potential (MMP), an increase in intracellular reactive oxygen species (ROS) and overexpression of inducible nitric oxide synthase (iNOS). The selective iNOS inhibitor AG partly blocked MPP(+)-induced apoptosis of PC12 cells. The results of present study suggested that the cytoprotective effects of curcumin might be mediated, at least in part, by the Bcl-2-mitochondria-ROS-iNOS pathway. Because of its non-toxic property, curcumin could be further developed to treat the neurodegenerative diseases which are associated with oxidative stress, such as Parkinson's disease (PD).

Wu RM, Bounds R, Lincoln S, Hulihan M, Lin CH, Hwu WL, Chen J, Gwinn-Hardy K, Farrer M. · Department of Neurology, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan. · Arch Neurol. · Pubmed #15642853 links to  free full text

Abstract: BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic "parkin-proven" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific.

Chen J, Guo J, Sun J, Jiang W, Wu B. · First Affiliated Hospital, Fourth Military Medical University, Shaanxi Province 710032. · J Tradit Chin Med. · Pubmed #14535173 No free full text.

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Chen J, Yang Z, Guo D, Niu H. · Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030. · J Huazhong Univ Sci Technolog Med Sci. · Pubmed #12658783 No free full text.

Abstract: From May, 2000 to June, 2001, 27 patients with Parkinson disease (PD), including 10 cases of rigidity, 13 cases of tremor, 4 cases of rigidity and tremor, were treated by microelectrode-guided technique. Among them, phlebotomy was carried out in 17 cases and thalamotomy in 10 cases. All the targets of lesion were anatomically located by using MR and neurophysiological signals on microelectrode. Our results showed that the efficiency of microelectrode-guided technique for treatment of PD was 98%. The postoperative unified parkinson disease rating scale were 12.3 +/- 9.1 and 13.2 +/- 8.9 respectively, which significantly improved as compared with those before operation. It was concluded that by recognizing special electrical signals in neurons microelectrode-guided neuropsychological techniques can locate target at cellular level, which overcomes the individual difference in anatomy and function, and allow more accuracy, safety and efficiency of operation. This is especially true of PD patients who fail to respond to medical treatment.

Chen J, Cao X, Xu Y, Sun S. · Department of Neurology, Xiehe Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022. · J Tongji Med Univ. · Pubmed #12539547 No free full text.

Abstract: To investigate the serum substantia nigra neuron autoantibody and its effect in the patients with Parkinson disease (PD), substantia nigra slices and a rat model of injection of serum from PD patients in unilateral side substantia nigra were applied. The results showed that the positive rate of substantia nigra neuron autoantibody in PD patients was significantly higher than in the healthy control group (36.67% vs 6.67%, P < 0.01), but no significant difference was found between PD group and myasthenia gravis (MG) group (26.67%, P > 0.05). The sera from PD patients positive for substantia nigra neuron autoantibody could decrease the number of the dopaminergic neurons more seriously than those from MG and the healthy once respectively (both P < 0.01). The results suggested that the immunological mechanism might partly play a role in the development of PD.

Wu RM, Shan DE, Sun CM, Liu RS, Hwu WL, Tai CH, Hussey J, West A, Gwinn-Hardy K, Hardy J, Chen J, Farrer M, Lincoln S. · Department of Neurology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei, Taiwan, Republic of China. · Mov Disord. · Pubmed #12210855 No free full text.

Abstract: We report on clinical (18)F-labeled 6-fluorodopa ((18)F-dopa) positron emission tomography (PET) and molecular genetic analyses of an ethnic Chinese family in which three siblings presented with early-onset Parkinson's disease. As described in some parkin patients, neither sleep benefit nor diurnal fluctuation was noted. Interestingly, depression, anxiety, and obsessive-compulsive disorders were manifest. The (18)F-dopa PET scans showed bilateral presynaptic dopaminergic dysfunction without marked lateralization. Molecular genetic analysis showed identical chromosome 6 haplotypes inherited by affected subjects, with alternate allelic deletions of parkin exons 3 and 4. Furthermore, mRNA analyses identified aberrantly spliced parkin transcripts, suggesting that unusual parkin protein isoforms may be expressed in the brain and retain some function.