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Wang C.,Capital Medical University | Wang C.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Cai Y.,Capital Medical University | Cai Y.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | And 11 more authors.
Parkinsonism and Related Disorders | Year: 2012

Variants in the LRRK2 gene are well-characterized genetic predisposing factors for PD worldwide, and LRRK2-associated PD is often indistinguishable from idiopathic PD (IPD). However, considerable heterogeneity of LRRK2-PD suggests the existence of additional genetic and/or environmental modifiers for LRRK2 carriers, which have yet to be confirmed by large-scale human studies. In a Chinese cohort consisting of 2013 sporadic PD patients and 1971 controls, we investigated the modification of the two Asian-specific LRRK2 variants, G2385R and R1628P, by variants of five other PD-associated genes/loci (SNCA, MAPT, GBA, BST1, PARK16). Of all the PD patients, 13.1% carried LRRK2 G2385R and/or R1628P variant. Among these carriers, a total of 15 different polygenic genotypes were detected representing different combination patterns between LRRK2 variants and those of the other genes/loci, which, alone or in combination, significantly modified the LRRK2-related risk for PD and the patients' ages at onset (AAOs). These results not only represent the largest replication data affirming the association between PD and all the six genes/loci in Chinese, but for the first time suggest that multiple PD-associated genetic factors modify both the penetrance and AAO of LRRK2 parkinsonism. This finding may have important implications for elucidating pathophysiologic mechanisms relevant to both LRRK2-associated and idiopathic PD. However, testing interactions among multiple genes by genetic association studies is still challenging. Future studies with much larger sample sizes are needed to confirm our findings. © 2012 Elsevier Ltd.

Wang C.,Capital Medical University | Wang C.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Wang C.,Fujian Medical University | Cai Y.,Capital Medical University | And 13 more authors.
Neurobiology of Aging | Year: 2014

Clinical profiles of Parkinson's disease (PD) related to LRRK2 (LRRK2-PD), and GBA (GBA-PD) genes have not been reported in Chinese individuals. In this study, we have investigated motor and non-motor aspects in 1638 Chinese PD patients who carried LRRK2 G2385R or R1628P (LRRK2-PD, n= 223), GBA L444P variant (GBA-PD, n= 49), or none of the variants (idiopathic PD [IPD], n= 1366). As a result, age at onset and motor and non-motor features of LRRK2-PD patients were similar to IPD patients except for milder non-motor symptoms. In contrast, GBA-PD patients had a significantly younger age at onset and higher Unified Parkinson's Disease Rating Scale scores than LRRK2-PD and IPD patients. In addition, postural instability and gait disorders, motor complications, cognitive decline, hallucination, sexual dysfunction, and constipation were more frequent in GBA-PD than in LRRK2-PD and IPD patients, and GBA-PD patients had a worse performance for social functioning and role-emotional scores. Our study represents the first large-scale clinical study of LRRK2-PD and GBA-PD in ethnic Chinese individuals. The data suggest that both LRRK2-PD and GBA-PD are similar to IPD, except for an earlier age at onset and relatively more common non-motor symptoms in GBA-PD patients. These findings strengthen our understanding of the clinical heterogeneity of PD, and may have implications for molecular classification of the disease. © 2014 Elsevier Inc.

Wang C.,Capital Medical University | Wang C.,Beijing Institute for Brain Disorders Parkinsons Disease Center | Wang C.,Fujian Medical University | Xu Y.,University of Sichuan | And 10 more authors.
Neurobiology of Aging | Year: 2014

CAG expansion within the exon 1 of ataxin-2 (ATXN2) gene responsible for spinocerebellar ataxia-2 (SCA2) has been reported to cause pure parkinsonism and other neurodegenerative disorders. However, it remains unclear whether CAG expansion is the only cause for SCA2 and its clinical alternatives, and whether extra mutations exist to modify the phenotypic diversity. To address this, we have conducted fine genetic mapping and exome sequencing for a large Chinese SCA2 pedigree predominantly manifesting parkinsonism (called SCA2-P). In addition, we compared the CAG expansions between the SCA2-P and 16 SCA2 families presenting as pure ataxia (SCA2-A). As a result, CAG repeat expansions, ranging from 37 to 40 copies, were detected among 10 affected and 8 nonsymptomatic members of the SCA2-P family. The CAG repeats in the diseased alleles were interrupted by CAA in the 3′-end. In contrast, CAG expansion ranging from 36 to 54 without CAA interruption was detected in all probands of the SCA2-A families. Genetic mapping located the SCA2-P pedigree on 12q24.21, which spans the ATXN2 gene. Exome sequencing for 3 patients and 1 normal member revealed no extra mutations in this family. In addition, by genotyping single-nucleotide polymorphisms around SCA2 locus, we have excluded the existence of haplotypes predisposing different patterns of CAG expansion. These results demonstrate that the ATXN2 CAG expansion is the sole causative mutation responsible for SCA2-P, and that genetic modifiers may not be the major cause of the phenotypic diversity of SCA2. © 2014 Elsevier Inc. All rights reserved.

Yue F.,Capital Medical University | Yue F.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Lu C.,WinconTheraCells Biotechnologies Co LTD | Ai Y.,University of Kentucky | And 3 more authors.
Neurobiology of Aging | Year: 2014

Nonhuman primates (NHPs) are useful for the study of age-associated changes in the brain as a model that is biologically closely related to humans. For example, with age, all NHPs analyzed to date, develop β-amyloid (Aβ) plaques as seen in humans. Nevertheless, it is still unclear if NHPs have human-like age-associated changes in Aβ and tau protein in cerebrospinal fluid. The present study was an attempt to specifically address these issues. Cerebrospinal fluid levels of Aβ and phosphorylated tau were measured in 37 and 22 cynomolgus monkeys, respectively, with ages ranging from 4 to 22-year-old. The result from the present study revealed significant age-associated declines in Aβ42 levels but not in Aβ40 and phosphorylated tau levels. This finding appears to parallel changes seen with human aging, in which decreased levels of Aβ42 can be seen in normal older adults, and supporting that cynomolgus monkeys would be a useful model for studying age-related neurologic disorders associated with Alzheimer-like cerebral proteopathy. © 2014 Elsevier Inc.

Wang C.,Capital Medical University | Wang C.,Key Laboratory on Neurodegenerative Disease of Ministry of Education | Wang C.,Key Laboratory on Parkinsons Disease of Beijing | Wang C.,Fujian Medical University | And 10 more authors.
Neurobiology of Aging | Year: 2013

Genome-wide association and large-scale replication studies have linked Parkinson's disease (PD) to a locus on 4p15 encompassing a single gene encoding bone marrow stromal cell antigen 1 (BST1). To screen for causative mutations of BST1 in PD, we have directly sequenced all the 9 exons of BST1 in a Chinese cohort consisting of 524 PD cases and 527 controls. As a result, 6 known and 1 novel single-nucleotide polymorphisms (SNPs) were identified in exons 1, 3, 4, 7, and 9. However, none of these SNPs were associated with PD. The data, together with previous reports, suggested that the association between BST1 and PD might be determined by the noncoding sequences of the gene. © 2013 Elsevier Inc.

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