Co-Existence of tau and α-synuclein pathology in fetal graft tissue at autopsy: A case report

IntroductionTransplant of fetal ventral mesencephalic tissue into the striatum of Parkinson's disease (PD) patients has been performed to increase dopamine production and stimulate neuronal regeneration. Analysis of fetal graft tissue at autopsy has demonstrated 6 cases of α-synuclein pathology in PD patients, one case with both α-synuclein and tau pathology in a PD patient, and two cases of tau pathology within a Huntington's Disease patient.MethodsA 49 year old man with PD underwent bilateral fetal ventral mesencephalic cell transplants into the striatum. Autopsy at age 70 included immunohistochemical staining of host and graft tissue with antibodies to phosphorylated α-synuclein and phosphorylated tau protein.ResultsAutopsy confirmed the diagnosis of PD. Immunohistochemical staining of graft tissue demonstrated frequent neuronal perikaryal inclusions of phosphorylated α -synuclein and tau in the left graft only.ConclusionSpeculations on the formation of pathology include: 1) α-synuclein and tau pathology spread from host to the graft in a neuron-neuron manner. 2) The nature of the fetal cells themselves, or transplantation process, may render fetal tissue more susceptible to the spontaneous generation of pathology. 3) Factors within host environment caused native tau and α-synuclein in fetal tissue graft to become phosphorylated.     

Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease

IntroductionUbiquitous naturally occurring autoantibodies (nAbs) against alpha-synuclein (α-syn) may play important roles in the pathogenesis of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Recently, we reported reduced high-affinity/avidity anti-α-syn nAbs levels in plasma from MSA and PD patients, along with distinct inter-group immunoglobulin (Ig)G subclass distributions. The extent to which these observations in plasma may reflect corresponding levels in the cerebrospinal fluid (CSF) is unknown.MethodsUsing competitive and indirect ELISAs, we investigated the affinity/avidity of CSF anti-α-syn nAbs as well as the CSF and plasma distribution of IgG subclasses and IgM nAbs in a cross-sectional cohort of MSA and PD patients.ResultsRepertoires of high-affinity/avidity anti-α-syn IgG nAbs were reduced in CSF samples from MSA and PD patients compared to controls. Furthermore, anti-α-syn IgM nAb levels were relatively lower in CSF and plasma from MSA patients but were reduced only in plasma from PD patients. Interestingly, anti-α-syn IgG subclasses presented disease-specific profiles both in CSF and plasma. Anti-α-syn IgG1, IgG2 and IgG3 levels were relatively increased in CSF of MSA patients, whereas PD patients showed increased anti-α-syn IgG2 and reduced anti-α-syn IgG4 levels.ConclusionsDifferences in the plasma/CSF distribution of anti-α-syn nAbs seem to be a common feature of synucleinopathies. Our data add further support to the notion that MSA and PD patients may have compromised immune reactivity towards α-syn. The differing α-syn-specific systemic immunological responses may reflect their specific disease pathophysiologies. These results are encouraging for further investigation of these immunological mechanisms in neurodegenerative diseases.     

苯并[a]芘对脑内多巴胺能神经元和α-突触核蛋白的影响及其机制

目的 分析苯并[a]芘[benzo(a)pyrene,BaP]暴露对帕金森病病理特征多巴胺能神经元和α-突触核蛋白表达的影响,并探讨可能的机制。方法 8月龄人源SNCA转基因小鼠随机分为BaP染毒组和对照组,分别腹腔注射1.0 mg/kg体质量的BaP和玉米油溶剂,连续注射60 d。通过转轮实验观察小鼠运动功能障碍状况,通过免疫组织化学与免疫蛋白印迹实验观察BaP对多巴胺能神经元和α-突触核蛋白的影响,采用实时荧光定量PCR法检测相关mRNA的表达。研究中涉及的基因主要与神经递质转运蛋白、神经递质受体、细胞自噬和α-突触核蛋白聚集与降解相关。结果 BaP染毒后,转轮实验中小鼠运动时间显著降低(P<0.05),小鼠黑质多巴胺能神经元明显减少,为对照组的62%(P<0.05),中脑α-突触核蛋白表达增多,为对照组的1.36倍(P<0.05)。BaP染毒后,小鼠中脑14种mRNA表达显著下调(P均<0.05),主要涉及α-突触核蛋白降解与细胞自噬、神经元转运体、神经递质受体等功能;而Synphilin-1表达显著上调(P<0.01),与α-突触核蛋白合成有关。结论 BaP暴露抑制神经递质受体、多巴胺转运体蛋白功能和细胞自噬作用,阻碍α-突触核蛋白降解,从而诱导黑质多巴胺能神经元变性死亡和α-syn聚集体形成,增加帕金森病发病风险。     

The diagnostic utility of cerebrospinal fluid alpha-synuclein analysis in dementia with Lewy bodies – A systematic review and meta-analysis

BackgroundDementia with Lewy Bodies (DLB) can be difficult to distinguish clinically from other dementias.ObjectiveTo investigate the diagnostic utility of CSF alpha-synuclein in differentiating between DLB and other dementias.MethodsElectronic databases were systematically searched for studies investigating reproducible alpha synuclein quantification methods. Random effects model was used to calculate weighted mean difference (WMD) and 95% confidence intervals between DLB and other groups.ResultsA total of 13 studies, comprising 2728 patients were included. Mean CSF alpha-synuclein concentration was significantly lower in DLB patients compared to those with Alzheimers disease (AD) [WMD ?0.24; 95% CI, ?0.45, ?0.03; p = 0.02]. No significant difference was found between patients with DLB compared to Parkinsons disease [WMD 0.05; 95% CI, ?0.17, 0.28; p = 0.65] or other neurodegenerative conditions.ConclusionCSF alpha synuclein may be of diagnostic use in differentiating between DLB and AD. We propose several recommendations to guide better design of future studies.     

A model of nitric oxide induced α-synuclein misfolding in Parkinson's disease

Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson's disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (α-syn). Moreover, nitration of α-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic α-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and α-syn AAV constructs led to nitration of α-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD.     

Lack of association of polymorphism in miRNA-196a2 with Parkinson's disease risk in a Chinese population

MicroRNAs (miRNAs) are a new class of non-protein coding RNA molecules, which participate in diverse biological pathways. We hypothesized that miRNA-196a2 polymorphism is associated with the risk of Parkinson's disease (PD) in a Chinese population. In a case-control study of 549 PD patients and 736 control subjects frequency matched by age and gender, we genotyped the single-nucleotide polymorphism (SNP) rs11614913 (T>C) in miRNA-196a2, whose target mRNA was alpha-synuclein, and assessed its association with risk of PD by TaqMan Genotyping method. No association was found for the miR-196a2 rs11614913 CT/CC genotype (odds ratio (OR), 0.879, 95% confidence interval (CI), 0.681-1.135 for CT genotype; OR, 1.085, 95% CI, 0.793-1.484 for CC genotype) with risk of PD, compared with the TT genotype. These results suggest that SNP rs11614913 in miRNA-196a2 may not contribute to the susceptibility to PD.     

Pathophysiology of Parkinson's disease: Mitochondria,alpha-synuclein and much more…

Parkinson's disease (PD) is a complex, age-related, neurodegenerative disease whose pathogenesis remains incompletely understood. Here, we give an overview of the progress that has been made over the past four decades in our understanding of this disorder. We review the role of mitochondria, environmental toxicants, alpha-synuclein and neuroinflammation in the development of PD. We also discuss more recent data from genetics, which strongly support the endosomal-lysosomal pathways and mitophagy as being central to PD. Finally, we discuss the emerging role of the gut-brain axis as a modulator of PD progression. This article is intended to provide a comprehensive, general and practical review of PD pathogenesis for the general neurologist.     

Effects of Genetic Background,Gender, and Early Environmental Factors on Isolation-Induced Ultrasonic Calling in Mouse Pups: An Embryo-Transfer Study

Infant rodents emit ultrasonic vocalizations when isolated from dam and littermates. Due to the context of their occurrence and the well described bidirectional modulation by substances known for their capability to influence emotionality, it was postulated that such calls reflect a negative affective state akin anxiety. Comparative studies observed pronounced differences in calling behavior between strains, which were paralleled by differences in maternal care. Therefore, it was recently hypothesized that early environmental factors may have strong impact on call production. Here, the relative contributions of genetic background, gender, and early environmental factors on calling behavior in C57BL/6JOlaHsd and C57BL/6NCrl were studied by using an embryo-transfer procedure. The results show that these sub-strains differ in the amount of calling and specific call features, like call frequency and amplitude. The embryo-transfer procedure indicated that the observed differences in the amount of ultrasonic calling are dependent on the dyadic interaction between mother and pup. Conversely, call features were primarily dependent on the genotype of the pup. Thus, call frequency and frequency modulation were solely dependent on the pup, i.e. its genotype and gender. However, there was one exception, namely call amplitude, which was solely dependent on the genotype of the mother, i.e. on early environmental factors. Furthermore, it was shown that particularly changes in call amplitude might be of high functional relevance, since a sub-strain dependent preference towards pups emitting calls with high amplitudes was observed. In total, it can be concluded that both genomic and nongenomic factors can tune calling behavior in mouse pups.     

A new perspective in Parkinson's disease, chaperone-mediated autophagy

Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by loss of dopaminergic neurons and aggregation of alpha-synuclein. Although the role of alpha-synuclein in the pathology of PD is still unclear, the fact that its aggregation contributes to the loss of dopaminergic neurons has been confirmed. Therefore, controlling the alpha-synuclein protein level may be critical for PD pathogenesis and may provide potential therapeutics. Wild-type alpha-synuclein is physiologically degraded by chaperone-mediated autophagy (CMA), and dysfunction of CMA results in alpha-synuclein aggregation and compensative macroautophagy activation which finally leads to cell death. Therefore, CMA may participate in PD pathogenesis as a very important factor, and up-regulating CMA activity could degrade overloaded alpha-synuclein. In view of potential compensative effects, maintenance of the balance of CMA activity will be another major challenge in the future development of the therapeutic strategy. Herein we review the current knowledge of the role of CMA in PD.