Alpha-synuclein and Parkinson disease

OBJECTIVE： To review the recent progresses on the studies of α -synuclein in the pathogenesis of Parkinson disease （PD） and look into the perspective of α -synuclein as a new therapy target. DATA SOURCES： To search the literatures on the progresses of PD studies, especially on the structure, gene expression of α-synuclein and the pathogenesis of PD in Medline from January 1998 to February 2007. Search terms were ＂Parkinson＇s disease, α-synuclein＂ in English. STUDY SELECTION： Initial check the data and choose the original and review articles directly linked to the role of α-synuclein in PD pathogenesis and screening out indirectly discussing articles. Collect the full text and trace the quoting articles and the quoted articles. Only the latest reviews were chosen in Chinese articles. DATA EXTRACTION： There were 424 articles on α-synuclein and its role in the pathogenesis of PD and 43 articles directly related with α-synuclein were chosen among which 12 were reviews. DATA SYNTHESIS： α-synuclein is a kind of soluble protein expressed in pre-synapse in central nervous system encoded by gene in homologous chromosome 4q21. It has physiological function in modulating the stability of membrane and neural plasticity. There is a close relationship between gene mutation in α -synuclein and the pathogenesis of PD. Environmental and genetic factors can induce the misfolding of α-synuclein, and secondary structural change can result in oligomer formation which induces a series of cascade reaction to damage dopaminergic system subsequently. Cell and animal transgenic and non-transgenic models are established recently and the important role of α-synuclein in the pathogenesis both of familial and sporadic PD is confirmed. Studies reveal that inhibiting the aggregation of α-synuclein can prevent its neurotoxicity; gene parkin can intercept the cell death pathway triggered by the aggregation of α-synuclein in cytoplasm. CONCLUSION： Gene mutation ofα-synuclein and the impairment in its structure and function are important in the pathogenesis of PD. Intervention of the gene mutations and abnormal protein aggregation ofα-synuclein may be a new strategy for preventing and treating PD.

Alpha-tubulin deacetylase as a potential and novel target for the prevention of Parkinson's disease progression

Parkinson＇s disease （PD） is the second most common neurodegenerative disorder and is characterized by its progressive course. The current therapies are aimed at alleviating symptoms by rescuing the unbalanced physiological dopamine metabolism and recovery of damaged neuronal circuits. However, these strategies result in insufficient clinical benefits for many patients and fail to halt disease progression. Therefore, new therapeutic targets could serve as the gateway against PD degeneration. One pathological hallmark of PD is the formation of intracytoplasmic protein inclusions or Lewy bodies, in neurons. Recent studies have suggested that Lewy bodies are formed similarly to aggresomes, and results have supported the concept that the novel cellular organelle, the aggresome, is a cytoprotective response that sequesters and facilitates clearance of potentially toxic protein aggregates. In addition, a-tubulin deacetylase has been shown to regulate aggresome formation and rescue neural cell viability in response to misfolded protein. Therefore, the regulation of aggresome formation to trigger cellular self-protection system could arrest PD progression. The present study discusses research progress related to Lewy bodies, aggresomes, and histone deacetylases, with an emphasis on histone deacetylase 6 and sirtuin type 2.

Parkinson’s disease: how should we consider the selectivity and progressivity of its neuropathology?

Parkinson’s disease(PD)is a common age-related neurodegenerative disease characterized by movement disorders.The hallmark pathological lesions of PD are the formation of Lewy pathology in selected populations of neurons throughout the nervous system.Braak and his colleagues created a staging system for PD describing the connection between Lewy pathology and disease severity.They proposed that Lewy pathology might be initially triggered by exogenous pathogens targeting the enteric or olfactory nervous system,then spread in a prion-like propagation manner from the peripheral nerves to the lower brainstem and midbrain,before finally reaching higher cortical structures,causing a sequential occurrence of the non-motor and motor symptoms,depending on the lesioned neurons.However,emerging evidence also supports a functional threshold hypothesis proposed by Engelender and Isacson in which Lewy pathology may occur parallelly in the central and peripheral nervous systems and the symptoms only begin when the functional reserve of the affected neurons(and their connecting brain regions)is unable to allow for network compensation.Consequently,early symptoms of PD reflect the loss of function in the least compensated systems,such as the enteric and olfactory nervous systems,rather than the spread of Lewy pathology from the peripheral to the central nervous systems.The current review article provides a comprehensive overview of the evidence supporting a merged mechanism that the neurodegeneration in PD happens to those neurons that are not only intrinsically vulnerable but also affected by the spread of Lewy pathology.

Alpha-synuclein truncation and disease

Alpha-synuclein is the major component of Lewy bodies, insoluble protein aggregates, found in patients with Parkinson’s disease, diffuse Lewy body disease, and the Lewy body variant of Alzheimer’s disease. Alpha-synuclein has been found within Lewy bodies to contain many different modifications, including nitration, phosphorylation, ubiquitination, and truncation. C-terminally truncated forms of alpha-synuclein aggregate faster than the full-length protein in vitro, and are thus believed to play a role in Lewy body formation and disease progression. Pathological studies of post mortem brain tissue and the generation of transgenic mouse models further support a role of C-terminally truncated forms of alpha-synuclein in disease. Several enzymes, some of which function extracellularly, have been implicated in the production of these C-terminally truncated forms of alpha-synuclein. However, the enzymes responsible for alphasynuclein truncation in vivo have not yet been firmly established.

Neurofilament light chain is increased in the parahippocampal cortex and associates with pathological hallmarks in Parkinson’s disease dementia

Background Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders.In this study,we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson’s disease(PD),PD with dementia(PDD)and dementia with Lewy bodies(DLB)donors,and its association with pathology load and MRI measures of atrophy and diffusivity.Methods Using a within-subject post-mortem MRI-pathology approach,we included 9 PD,12 PDD/DLB and 18 age-matched control donors.Cortical thickness and mean diffusivity(MD)metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI.After autopsy,pathological hallmarks(pSer129-αSyn,p-tau and amyloid-βload)together with neurofilament light-chain(NfL)and phosphorylated-neurofilament medium-and heavy-chain(p-NfM/H)immunoreactivity were quantified in seven cortical regions,and studied in detail with confocal-laser scanning microscopy.The correlations between MRI and pathological measures were studied using linear mixed models.Results Compared to controls,p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB,whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB.NfL-positive neurons showed degenerative morphological features and axonal fragmentation.The increased p-NfM/H correlated with p-tau load,and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB.Lastly,neuro-filament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB.Conclusions Taken together,increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden.Importantly,we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process.

Knowledge domain and emerging trends in visual hallucination research:A scientometric analysis

BACKGROUND Visual hallucination(VH)refers to a spontaneous visual perception without corresponding external stimuli and often occurs in ophthalmological and neuropsychiatric disorders.It is associated with poor quality of life,and increased patient hospitalization and nursing home admission.To date,a scientometric analysis of research on VH is lacking.AIM To objectively summarize the features of VH research and gain insights into the emerging trends in research on VH.METHODS CiteSpace V was used in this article.Publication outputs,document types,geographic distributions,co-authorship status,research hotspots,and co-citation status were analyzed.A total of 2176 original articles and 465 reviews were included in the database downloaded from the Web of Science Core Collection.We selected the top 50 most cited or occurring articles or items to create a visualized network with a 1-year interval.In the document co-citation analysis stage,we performed clustering analysis on co-cited references,and log likelihood tests were used to name the clusters.RESULTS The results showed that most publications can be classified into neurology,sports,and ophthalmology studies.In addition,North America,Europe,Asia and Australia published the most documents.Some well-known authors have always had a leading role in this field;meanwhile,new authors keep emerging.A relatively stable cooperation has been formed among many authors.Furthermore,neuropsychiatric symptom and functional connectivity are the top hotspots.Research on VH in dementia with Lewy bodies and Parkinson’s disease(PD)have received much attention.Studies on VH in PD are likely to be the new emerging trends in the future,especially the mechanisms of VH.CONCLUSION Research on VH has formed a complete system.More large-scale clinical and indepth basic research are required to better understand the mechanisms underlying VH,which will contribute to our understanding of the pathophysiology and therapeutic options for VH.

The role of quercetin on the survival of neuron-like PC12 cells and the expression of α-synuclein

Both genetic and environmental factors are important in the pathogenesis of Parkinson＇s disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson＇s disease, genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin（100, 500, 1,000 μM） and then together with various drugs such as 1-methyl-4-phenylpyridinium（MPP＋; a free radical generator）, 6-hydroxydopamine（6-OHDA; a free radical generator）, ammonium chloride（an autophagy inhibitor）, and nocodazole（an aggresome inhibitor）. Cell viability was determined using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltertazolium bromide（MTT） assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations（100 and 500 μM） of quercetin but decreased at higher concentration（1,000 μM）. Quercetin exerted neuroprotective effect against MPP＋, ammonium chloride and nocodazole at 100 μM. MPP＋ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson＇s disease pathogenesis needs further investigation.

Relationships between Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases： Clinical Assessments, Biomarkers, and Treatment

Objective： Rapid eye movement sleep behavior disorder （RBD） is characterized by dream enactment and loss of muscle atonia during rapid eye movement sleep. RBD is closely related to α-synucleinopathies including Parkinson＇s disease, dementia with Lewy bodies, and multiple system atrophy. Many studies have investigated the markers of imaging and neurophysiological, genetic, cognitive, autonomic function of RBD and their predictive value for neurodegenerative diseases. This report reviewed the progress of these studies and discussed their limitations and future research directions. Data Sources： Using the combined keywords： ＂RBD＂, ＂neurodegenerative disease＂, ＂Parkinson disease＂, and ＂magnetic resonance imaging＂, the PubMed/MEDLINE literature search was conducted up to January 1, 2018. Study Selection： A total of 150 published articles were initially identified citations. Of the 150 articles, 92 articles were selected after further detailed review. This study referred to all the important English literature in full. Results： Single-nucleotide polymorphisms in SCARB2 （rs6812193） and MAPT （rs12185268） were significantly associated with RBD. The olfactory loss, autonomic dysfunction, marked electroencephalogram slowing during both wakefulness and rapid eye movement sleep, and cognitive impairments were potential predictive markers for RBD conversion to neurodegenerative diseases. Traditional structural imaging studies reported relatively inconsistent results, whereas reduced functional connectivity between the left putamen and substantia nigra and dopamine transporter uptake demonstrated by functional imaging techniques were relatively consistent findings. Conclusions： More longitudinal studies should be conducted to evaluate the predictive value of biomarkers of RBD. Moreover, because the glucose and dopamine metabolisms are not specific for assessing cognitive cognition, the molecular metabolism directly related to cognition should be investigated. There is a need for more treatnaent trials to determine the effectiveness of interventions of RBD on preventing the conversion to neurodegenerative diseases.

Associated mortality risk of atypical antipsychotic medication in individuals with dementia

BACKGROUND Antipsychotic medications such as risperidone,olanzapine and aripiprazole are used to treat psychological and behavioural symptoms among dementia patients.Current evidence indicate prescription rates for antipsychotics vary and wider consensus to evaluate clinical epidemiological outcomes is limited.AIM To investigate the potential impact of atypical antipsychotics on the mortality of patients with dementia.METHODS A retrospective clinical cohort study was developed to review United Kingdom Clinical Record Interactive Search system based data between January 1,2013 to December 31,2017.A descriptive statistical method was used to analyse the data.Mini Mental State Examination(MMSE)scores were used to assess the severity and stage of disease progression.A cox proportional hazards model was developed to evaluate the relationship between survival following diagnosis and other variables.RESULTS A total of 1692 patients were identified using natural language processing of which,587 were prescribed olanzapine,quetiapine or risperidone(common group)whilst 893(control group)were not prescribed any antipsychotics.Patients prescribed olanzapine showed an increased risk of death[hazard ratio(HR)=1.32;95%confidence interval(CI):1.08-1.60;P<0.01],as did those with risperidone(HR=1.35;95%CI:1.18-1.54;P<0.001).Patients prescribed quetiapine showed no significant association(HR=1.09;95%CI:0.90-1.34;P=0.38).Factors associated with a lower risk of death were:High MMSE score at diagnosis(HR=0.72;95%CI:0.62-0.83;P<0.001),identifying as female(HR=0.73;95%CI:0.64-0.82;P<0.001),and being of a White-British ethnic group(HR=0.82;95%CI:0.72-0.94;P<0.01).CONCLUSION A significant mortality risk was identified among those prescribed olanzapine and risperidone which contradicts previous findings although the study designs used were different.Comprehensive research should be conducted to better assess clinical epidemiological outcomes associated with diagnosis and therapies to improve clinical management of these patients.

Mild cognitive impairment in Parkinson’s disease:a distinct clinical entity?

Background:Mild cognitive impairment in Parkinson’s disease(PD-MCI)is a common clinical condition.Understanding its pathology and clinical features is important for early intervention before the onset of dementia.In the past,variable definitions and differences in neuropsychological batteries generated divergent results of the affected cognitive patterns.Main body:The introduction of PD-MCI criteria by the Movement Disorders Society(MDS)Task Force provides a more uniform system for defining and measuring PD-MCI and may improve the validity of future research.PD-MCI is likely to be heterogeneous since it can coexist with Alzheimer’s disease and/or Lewy body pathologies in PD.Pathogeneses of neuropsychiatric disturbances,such as depression,anxiety and apathy,are associated with PD with or without MCI.In addition,cognitive reserve formed by patients’unique life experiences may influence the outward cognitive performance despite the presence of the aforementioned pathogeneses and hence alter the diagnosis of MCI.Conclusion:The overlap of cognitive impairment across different neurodegenerative diseases suggests that PD-MCI is likely to result from a mixture of complex pathophysiologies,rather than being a distinct pathologic entity.Differentiating MCI from other organic symptoms in PD would facilitate novel therapeutic strategies.

帕金森病路易(小)体的蛋白质生物信息学数据分析

原发性帕金森病(idiopathic Parkinson's disease,PD)的主要病理特征之一是出现于中脑特定脑区黑质致密部(substantia nigra pars compacta,SNpc)多巴胺能神经元的路易(小)体(Lewy bodies,LBs),PD病人LBs和/或路易轴突也出现于脑内其他脑区非多巴胺能神经元,比如蓝斑(locus coeruleus,LC)等脑干个别脑区去甲肾上腺素能神经元、额前叶皮层(prefrontal cortex,PFC)、颞叶皮层(temporal cortex,TC)等大脑多个脑区胆碱能神经元.为了明确LBs的蛋白质构成,本文通过蛋白质生物信息学数据分析,就LBs的蛋白质构成归纳了5个方面的要点:a.LBs的组织结构单元是α-突触核蛋白(α-synuclein,α-SYN)表征的2类纤维状聚集物和6类非纤维状聚集物(通常被称为寡聚物);b.病理性α-SYN在LBs内存在5种化学修饰形式;c.19个α-SYN相关蛋白质分别与α-SYN共定位于LBs;d.117个LBs的已知蛋白质被划分为10组不同蛋白质功能群组;e.LBs的蛋白质组学鉴定数据库包含了分别在LC、SNpc和PFC脑区组织水平鉴定的84、124和120个候选蛋白质,在TC脑区细胞水平鉴定的108个候选蛋白质,以及在TC脑区亚细胞水平鉴定的29个候选蛋白质.上述要点广泛、深入地概括了LBs的蛋白质构成.

路易体痴呆与帕金森病多模态功能磁共振比较研究

目的:探讨路易体痴呆(dementia with Lewy body,DLB)患者和帕金森病(Parkinson’s disease,PD)患者静息状态下脑结构及功能的改变。方法:对16例DLB患者、20例PD患者和20例正常者对照进行T1结构像、静息态功能磁共振扫描,比较3组间脑区局部一致性(regional homogeneity,Re Ho)和灰质体积(grey matter volume,GMV)的差异,并将差异与蒙特利尔认知评估量表(Montreal cognitive assessment,MOCA)、简易精神状态量表(mini mental state examination,MMSE)、统一的PD评分量表第三部分(unified Parkinson’s disease rating scale-Ⅲ,UPDRS-Ⅲ)进行相关分析。结果:(1)与对照组比较,DLB组左侧小脑前叶、双侧距状裂、双侧尾状核Re Ho增高,左侧额中回Re Ho减低;PD组右侧颞上回、右侧缘上回Re Ho增高;与PD组比较,DLB组双侧尾状核Re Ho增高,右侧缘上回、左侧额下回Re Ho减低。(2)与对照组比较,DLB组双侧尾状核、右侧颞叶GMV减少;与PD组比较,DLB组右侧尾状核、右侧颞叶GMV减少。(3)DLB组双侧尾状核Re Ho值与UPDRS-Ⅲ评分呈负相关。结论:DLB患者静息态下脑结构和功能发生改变,这些改变可能与疾病的病理生理机制有关。

α-突触核蛋白相互作用的蛋白在帕金森病发病中的作用

帕金森病(Parkinson’s disease,PD)的主要病理特征是中脑黑质致密部多巴胺能神经元的选择性变性、死亡,以及在残存的神经元胞浆中出现以α-突触核蛋白(alpha-synuclein,α-SYN)为主要成分的淀粉样蛋白包涵体——Lewy小体。已有大量研究证据表明,α-SYN的异常聚集在PD的发病和Lewy小体的形成中发挥了关键作用,而parkin、synphilin-1、14-3-3、agrin、tau等蛋白通过与α-SYN相互作用影响了α-SYN的异常聚集。

突触小体相关蛋白-25在神经退行性疾病中的研究进展

突触功能障碍是神经退行性疾病中神经退行性变的重要病理机制之一,检测突触蛋白生物标志物在判定疾病进展及监测疾病修饰药物的临床疗效中具有重要价值。突触小体相关蛋白-25是突触前质膜蛋白,能准确反映神经退行性疾病中发生的突触损伤,是目前十分有前景的评估突触功能的生物标志物。本文现围绕突触小体相关蛋白-25的基本特征、功能及其在阿尔茨海默病、帕金森病、路易体相关痴呆等神经退行性疾病中的研究进展进行综述,以期为在临床前阶段早期识别高危患者的病理改变、监测患者病情进展以及开发新的治疗靶点提供参考依据。

Beyond the synucleinopathies:alpha synuclein as a driving force in neurodegenerative comorbidities

The fundamental role that alpha-synuclein(aSyn)plays in the pathogenesis of neurodegenerative synucleinopathies,including Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy,is a well-accepted fact.A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain.Beyond the synucleinopathies,the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease.In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception,the potential role that aSyn may have in these disorders has received relatively little attention.In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities.In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies,we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins,including tau,TDP-43,amyloid-βand prion protein,in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology.We conclude that a growing body of evidence,encompassing neuropathology studies in human brain,animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction,cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities.We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases.

Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy

Background: Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Methods: Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau−/− mice to generate TgA53T/mTau−/−. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau−/−, and mTau−/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Results: Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Conclusions: Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.