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. Source
Chen M.,Capital Medical University |
Chen M.,Guilin Medical University |
Wang T.,Capital Medical University |
Yue F.,Capital Medical University |
And 7 more authors.
Neuroscience | Year: 2015
Tea polyphenols (TPs) are bioactive flavanol-related catechins that have been shown to protect dopaminergic (DAergic) neurons against neurotoxin-induced injury in mouse Parkinson's disease (PD) models. However, the neuroprotective efficacy of TP has not been investigated in nonhuman PD primates, which can more accurately model the neuropathology and motor impairments of human PD patients. Here, we show that oral administration of TP alleviates motor impairments and DAergic neuronal injury in the substantia nigra in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated PD monkeys, indicating an association between protection against motor deficits and preservation of DAergic neurons. We also show a significant inhibition of MPTP-induced accumulation of neurotoxic α-synuclein (α-syn) oligomers in the striatum and other brain regions, which may contribute to the neuroprotection and improved motor function conferred by TP. The association between reduced α-syn oligomerization and neuroprotection was confirmed in cultured DAergic cells. The most abundant and bioactive TP in the mixture used in vivo, (-)-epigallocatechin-3-gallate, reduced intracellular levels of α-syn oligomers in neurons treated with α-syn oligomers, 1-methyl-4-phenylpyridiniumion, or both, accompanied by increased cell viability. The present study provides the first evidence that TP can alleviate motor impairments, DAergic neuronal injury, and α-syn aggregation in nonhuman primates. © 2014 IBRO. Source
Chen Y.,Capital Medical University |
Yang W.,Capital Medical University |
Li X.,Capital Medical University |
Yang H.,Capital Medical University |
And 5 more authors.
Neuroscience | Year: 2015
Abnormal α-synuclein (α-syn) expression and aggregation have been implicated in the pathogenesis of Parkinson's disease (PD), dementia with Lewy bodies (DLB), and Alzheimer's disease (AD). These neurodegenerative disorders, collectively known as synucleinopathies, are usually associated with cognitive impairment that could be caused by impaired hippocampal function. Although abnormal expressions of α-syn and N-methyl-d-aspartate (NMDA) receptor are frequently observed in the hippocampus of patients with synucleinopathies, how these proteins interact with each other in hippocampal neurons remains poorly understood. In the present study, primary cultures of hippocampal neurons and α-syn transgenic mice were used to investigate the effect of α-syn on NMDA receptors. Neurons were treated either by direct addition of recombinant human α-syn (hα-syn) to the medium, or by infection with the hα-syn gene, to increase intracellular levels of α-syn. In both cases, NMDA receptor NR1 subunits on the cell surface were reduced while the total amount of NR1 was unchanged, indicating an internalization of NR1 subunits. Neurons with elevated α-syn also showed a profound increase in Rab5B, an isoform of the small GTPases essential for NMDA receptor endocytosis. Knockdown of Rab5B expression by siRNA inhibited the α-syn-induced reduction in surface NR1. The in vitro findings were confirmed in α-syn transgenic mice, showing that increased α-syn expression was accompanied by reduced levels of surface NR1 and increased expression of Rab5B. Due to the essential role of NR1 subunits for assembling a complete NMDA receptor, its reduction on the cell surface indicated impaired receptor function. This was demonstrated by observations that neurons with elevated α-syn showed profound reductions in NMDA-elicited Ca2+ influx and inward current, which were also inhibited by knockdown of Rab5B expression. Our data suggest that increased α-syn expression may impair NMDA receptor function in the hippocampus by reducing the density of NR1 subunits on the cell surface. © 2015 IBRO. Source