博文
年终盘点：2019年帕金森病十大基础研究进展
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2019年帕金森病十大基础研究进展
1. Lancet Neurol—迄今为止最大的帕金森病全基因组关联研究（荟萃分析）报道了一系列帕金森病相关的风险基因位点
点评：这项研究综合了17个帕金森病GWAS研究数据库的所有数据，发现了90个全基因组显著的风险变异信号，这些信号横跨78个基因组区域。其中38个是全新的风险变异信号，位于37个基因组位点中。这90个风险变异可以解释帕金森病16%~36%的遗传风险。
英文摘要：
BACKGROUND:
Genome-wideassociation studies (GWAS) in Parkinson's disease have increased the scope ofbiological knowledge about the disease over the past decade. We aimed to usethe largest aggregate of GWAS data to identify novel risk loci and gain furtherinsight into the causes of Parkinson's disease.
METHODS:
Wedid a meta-analysis of 17 datasets from Parkinson's disease GWAS available fromEuropean ancestry samples to nominate novel loci for disease risk. Thesedatasets incorporated all available data. We then used these data to estimateheritable risk and develop predictive models of this heritability. We also usedlarge gene expression and methylation resources to examine possible functionalconsequences as well as tissue, cell type, and biological pathway enrichmentsfor the identified risk factors. Additionally, we examined shared genetic riskbetween Parkinson's disease and other phenotypes of interest via geneticcorrelations followed by Mendelian randomisation.
FINDINGS:
BetweenOct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotidepolymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individualswho do not have Parkinson's disease but have a first degree relative thatdoes), and 1·4 million controls. We identified 90 independent genome-widesignificant risk signals across 78 genomic regions, including 38 novelindependent risk signals in 37 loci. These 90 variants explained 16-36% of theheritable risk of Parkinson's disease depending on prevalence. Integratingmethylation and expression data within a Mendelian randomisation frameworkidentified putatively associated genes at 70 risk signals underlying GWAS locifor follow-up functional studies. Tissue-specific expression enrichmentanalyses suggested Parkinson's disease loci were heavily brain-enriched, withspecific neuronal cell types being implicated from single cell data. We foundsignificant genetic correlations with brain volumes (false discoveryrate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume),smoking status (p=0·024), and educational attainment (p=0·038). Mendelianrandomisation between cognitive performance and Parkinson's disease risk showeda robust association (p=8·00 × 10-7).
INTERPRETATION:
Thesedata provide the most comprehensive survey of genetic risk within Parkinson'sdisease to date, to the best of our knowledge, by revealing many additionalParkinson's disease risk loci, providing a biological context for these riskfactors, and showing that a considerable genetic component of this diseaseremains unidentified. These associations derived from European ancestrydatasets will need to be followed-up with more diverse data.
FUNDING:
TheNational Institute on Aging at the National Institutes of Health (USA), TheMichael J Fox Foundation, and The Parkinson's Foundation (see appendix for fulllist of funding sources).
参考文献：
Nallset al (2019). Identification of novel risk loci, causal insights, and heritablerisk for Parkinson's disease: a meta-analysis of genome-wide associationstudies. Lancet Neurol. 2019 Dec;18(12):1091-1102.
2. Nature—研究发现6个分子伴侣蛋白可识别α-synuclein并抑制α-synuclein的异常聚集
点评：这项研究的价值在于发现了6个α-synuclein的上游调控分子伴侣蛋白。这6个分子伴侣蛋白可以识别α-synuclein的N端从而抑制α-synuclein的聚集。研究人员发现抑制α-synuclein和HSC70及HSP90家族蛋白的相互作用导致了α-synuclein定位于线粒体并促进了其异常聚集。研究还发现了α-synuclein在Tyr39氨基酸位点的磷酸化损害了α-synuclein和伴侣蛋白的相互作用。这项研究揭示了分子伴侣蛋白调控α-synuclein细胞内定位及其聚集的分子机制，为开发靶向于分子伴侣蛋白通路的帕金森病治疗药物提供了有意义的启发。
英文摘要：
Neurodegenerationin patients with Parkinson's disease is correlated with the occurrence of Lewybodies-intracellular inclusions that contain aggregates of the intrinsicallydisordered protein α-synuclein1. The aggregation propensity of α-synuclein incells is modulated by specific factors that include post-translationalmodifications2,3, Abelson-kinase-mediated phosphorylation4,5 and interactionswith intracellular machineries such as molecular chaperones, although theunderlying mechanisms are unclear6-8. Here we systematically characterize theinteraction of molecular chaperones with α-synuclein in vitro as well as incells at the atomic level. We find that six highly divergent molecularchaperones commonly recognize a canonical motif in α-synuclein, consisting ofthe N terminus and a segment around Tyr39, and hinder the aggregation ofα-synuclein. NMR experiments9 in cells show that the same transient interactionpattern is preserved inside living mammalian cells. Specific inhibition of theinteractions between α-synuclein and the chaperone HSC70 and members of theHSP90 family, including HSP90β, results in transient membrane binding andtriggers a remarkable re-localization of α-synuclein to the mitochondria andconcomitant formation of aggregates. Phosphorylation of α-synuclein at Tyr39directly impairs the interaction of α-synuclein with chaperones, thus providinga functional explanation for the role of Abelson kinase in Parkinson's disease.Our results establish a master regulatory mechanism of α-synuclein function andaggregation in mammalian cells, extending the functional repertoire ofmolecular chaperones and highlighting new perspectives for therapeuticinterventions for Parkinson's disease.
参考文献：
Burmannet al (2019). Regulation of α-synuclein by chaperones in mammalian cells. Nature.2019 Dec 4.
3. Nature—肠道感染可诱发Pink1缺陷小鼠出现帕金森病样的症状
点评：这项研究的价值在于发现了外界环境因素对帕金森病表型的发生起到关键的作用。众所周知，人类PINK1突变或者缺失可引起帕金森病，然而在PINK1缺陷的帕金森病模型小鼠中，研究人员并未发现帕金森病样的行为学和病理表型。先前研究发现了PINK1缺陷可以诱导线粒体抗原的提呈和自身免疫反应。这项研究发现了革兰氏阴性菌感染可以促进PINK1缺陷小鼠的线粒体抗原提呈和线粒体特异的CD8+T细胞的扩增。因此，这项研究进一步确证了PINK1是免疫系统的抑制因子，同时也为肠道感染诱发帕金森病表型的猜测提供了佐证。
英文摘要：
Parkinson'sdisease is a neurodegenerative disorder with motor symptoms linked to the lossof dopaminergic neurons in the substantia nigra compacta. Although themechanisms that trigger the loss of dopaminergic neurons are unclear,mitochondrial dysfunction and inflammation are thought to have key roles1,2. Anearly-onset form of Parkinson's disease is associated with mutations in thePINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded byPRKN) are involved in the clearance of damaged mitochondria in cultured cells4,but recent evidence obtained using knockout and knockin mouse models have ledto contradictory results regarding the contributions of PINK1 and Parkin tomitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have akey role in adaptive immunity by repressing presentation of mitochondrialantigens9, which suggests that autoimmune mechanisms participate in theaetiology of Parkinson's disease. Here we show that intestinal infection withGram-negative bacteria in Pink1-/- mice engages mitochondrial antigenpresentation and autoimmune mechanisms that elicit the establishment ofcytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain.Notably, these mice show a sharp decrease in the density of dopaminergic axonalvaricosities in the striatum and are affected by motor impairment that isreversed after treatment with L-DOPA. These data support the idea that PINK1 isa repressor of the immune system, and provide a pathophysiological model inwhich intestinal infection acts as a triggering event in Parkinson's disease,which highlights the relevance of the gut-brain axis in the disease10.
参考文献：
Matheoudet al (2019). Intestinal infection triggers Parkinson's disease-like symptomsin Pink1-/- mice. Nature. 2019 Jul;571(7766):565-569.
4. Science—研究揭示了肠道微生物代谢左旋多巴并降低其药效的分子机制
点评：这项研究发现了粪肠球菌中磷酸吡哆醛依赖的酪氨酸脱羧酶可将肠道中的左旋多巴转变为多巴胺，然后多巴胺再被迟缓埃格特菌中钼依赖的脱羟基酶转变为间酪胺。而通过抑制酪氨酸脱羧酶的活性可以显著增加小鼠体内左旋多巴的生物利用率。这项研究揭示了肠道左旋多巴被肠道微生物代谢的分子机制，从而为临床上增加左旋多巴药物生物利用率提供了潜在的干预途径。
英文摘要：
Thehuman gut microbiota metabolizes the Parkinson's disease medication Levodopa(l-dopa), potentially reducing drug availability and causing side effects.However, the organisms, genes, and enzymes responsible for this activity inpatients and their susceptibility to inhibition by host-targeted drugs areunknown. Here, we describe an interspecies pathway for gut bacterial l-dopa metabolism.Conversion of l-dopa to dopamine by a pyridoxal phosphate-dependent tyrosinedecarboxylase from Enterococcus faecalis is followed by transformation ofdopamine to m-tyramine by a molybdenum-dependent dehydroxylase from Eggerthellalenta These enzymes predict drug metabolism in complex human gut microbiotas.Although a drug that targets host aromatic amino acid decarboxylase does notprevent gut microbial l-dopa decarboxylation, we identified a compound thatinhibits this activity in Parkinson's patient microbiotas and increases l-dopabioavailability in mice.
参考文献：
Maini et al (2019). Discovery and inhibition of aninterspecies gut bacterial pathway for Levodopa metabolism. Science. 2019 Jun 14;364(6445).
5. Neuron—Braak病理分级假说的“肠到脑途径”被证实：研究证明病理性的α-synuclein蛋白可从肠道经迷走神经扩散入帕金森病小鼠的脑内
点评：Braak假说解释了帕金森病病理发生和发展过程。该假说认为外周的α-synuclein病理蛋白可经肠道和鼻腔的神经纤维扩散入脑进而引起帕金森病。本研究的研究人员将α-synuclein预成型纤维注射入小鼠小肠和幽门的肌层中，然后动态的观察了α-synuclein如何从外周扩散入中枢。他们发现α-synuclein首先出现在迷走神经背核中，然后逐渐的依次出现于蓝斑核、基底外侧杏仁核、中缝背核和黑质致密部。随着病理的逐步扩散，他们也观察到了多巴胺能神经元的逐渐丢失和运动及非运动症状的出现。切断迷走神经干或者敲除α-synuclein可预防由肠道到脑的α-synuclein病理扩散、神经变性和行为缺陷。这项研究为α-synuclein的肠-脑扩散途径提供了直接的证据，为Braak假说的证实提供了较佳的实验证据。
英文摘要：
Analysisof human pathology led Braak to postulate that α-synuclein (α-syn) pathologycould spread from the gut to brain via the vagus nerve. Here, we test thispostulate by assessing α-synucleinopathy in the brain in a novel gut-to-brainα-syn transmission mouse model, where pathological α-syn preformed fibrils wereinjected into the duodenal and pyloric muscularis layer. Spread ofpathologic α-syn in brain, as assessed by phosphorylation of serine 129 ofα-syn, was observed first in the dorsal motor nucleus, then in caudal portionsof the hindbrain, including the locus coeruleus, and much later in basolateralamygdala, dorsal raphe nucleus, and the substantia nigra pars compacta.Moreover, loss of dopaminergic neurons and motor and non-motor symptoms wereobserved in a similar temporal manner. Truncal vagotomy and α-syn deficiencyprevented the gut-to-brain spread of α-synucleinopathy and associatedneurodegeneration and behavioral deficits. This study supports the Braakhypothesis in the etiology of idiopathic Parkinson'sdisease (PD).
参考文献:
Kimet al (2019). Transneuronal Propagation of Pathologic α-Synuclein from the Gutto the Brain Models Parkinson's Disease. Neuron. 2019 Aug 21;103(4):627-641.e7.
6. Cell stem cell—研究发现SATB1缺陷可诱导多巴胺能神经元的细胞衰老。
点评：细胞衰老是机体衰老的重要生物学机制。神经元是终末分化细胞，因此随着机体衰老，多巴胺能神经元也会逐渐的衰老。先前的研究发现衰老的细胞可以引起局部炎症并有害于周围的细胞。那么多巴胺能神经元衰老在神经变性中的作用是如何的呢？该研究发现SATB1可显著地抑制多巴胺能神经元的细胞衰老，而SATB1缺陷可激活多巴胺能神经元的细胞衰老。研究人员还发现了SATB1是通过抑制促衰老因子P21的表达进而抑制多巴胺能神经元的细胞衰老。这项研究为细胞衰老促进神经变性的假设提供了分子生物学证据。
英文摘要：
Cellularsenescence is a mechanism used by mitotic cells to prevent uncontrolled celldivision. As senescent cells persist in tissues, they cause local inflammationand are harmful to surrounding cells, contributing to aging. Generally,neurodegenerative diseases, such as Parkinson's,are disorders of aging. The contribution of cellular senescence toneurodegeneration is still unclear. SATB1 is a DNA binding protein associatedwith Parkinson's disease. We report that SATB1prevents cellular senescence in post-mitotic dopaminergic neurons. Loss ofSATB1 causes activation of a cellular senescence transcriptional program indopamine neurons both in human stem cell-derived dopaminergic neurons and inmice. We observed phenotypes that are central to cellular senescence in SATB1knockout dopamine neurons in vitro and in vivo. Moreover, we foundthat SATB1 directly represses expression of the pro-senescence factor p21 indopaminergic neurons. Our data implicate senescence of dopamine neurons as acontributing factor in the pathology of Parkinson'sdisease.
参考文献：
Riessland et al (2019). Loss of SATB1 Inducesp21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons. Cell Stem Cell. 2019 Oct 3;25(4):514-530.e8
7. Nat Cell Biol— Parkin是肿瘤抑制因子：AMPK-Parkin通过抑制坏死小体进而抑制坏死性凋亡和肿瘤发生
点评：这项研究发现了AMPK-Parkin轴是坏死性凋亡的负性调控机制。作者揭示了帕金森病致病基因Parkin竟是肿瘤抑制因子。此外，Parkin通过促进RIPK3的多聚泛素化从而抑制RIPK1-RIPK3复合体的形成。他们还发现Parkin可被AMPK磷酸化和激活。最后，他们揭示了Parkin缺陷可增强RIPK1-RIPK3相互作用，RIPK3磷酸化和坏死性凋亡，同时还可加剧炎症和炎症相关的肿瘤发生。这一系列的实验证据证明了AMPK-Parkin轴通过抑制RIPK1-RIPK3相互作用进而负性调控坏死性凋亡。
英文摘要：
Thereceptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 playimportant roles in necroptosis that are closely linked to the inflammatoryresponse. Although the activation of necroptosis is well characterized, themechanism that tunes down necroptosis is largely unknown. Here we find thatParkin (also known as PARK2), an E3 ubiquitin ligase implicated in Parkinson's disease and as a tumour suppressor,regulates necroptosis and inflammation by regulating necrosome formation.Parkin prevents the formation of the RIPK1-RIPK3 complex by promotingpolyubiquitination of RIPK3. Parkin is phosphorylated and activated by thecellular energy sensor AMP-activated protein kinase (AMPK). Parkin deficiencypotentiates the RIPK1-RIPK3 interaction, RIPK3phosphorylation and necroptosis. Parkin deficiency enhances inflammation andinflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis byinhibiting RIPK1-RIPK3 complex formation; this regulation may serve as an importantmechanism to fine-tune necroptosis and inflammation.
参考文献：
Leeet al (2019). The AMPK-Parkin axis negatively regulates necroptosis andtumorigenesis by inhibiting the necrosome. Nat Cell Biol. 2019Aug;21(8):940-951.
8. Cell stem cell—单细胞测序研究助力帕金森病药物的开发：HDAC4调节化合物可纠正帕金森病相关的细胞表型。
点评：iPSC（诱导多功能干细胞）来源的多巴胺能神经元为模拟帕金森病提供了极佳的细胞平台。通过对携带PD风险基因的iPSC分化的多巴胺能神经元进行单细胞转录组学测序，研究人员发现了引起内质网应激的差异性基因表达及其上游调控因子HDAC4。研究人员进一步发现HDAC4错误定位于PD来源多巴胺能神经元的细胞核内，通过抑制基因表达进而引起蛋白内稳态的缺陷。而给予HDAC4调节化合物上调基因表达可纠正帕金森病相关的细胞表型。
英文摘要：
Inducedpluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity tomodel Parkinson's disease (PD), but neuronalcultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution,single-cell transcriptomic analyses of iPSC-derived dopamine neurons carryingthe GBA-N370S PD risk variant, we identified a progressive axis of geneexpression variation leading to endoplasmic reticulum stress. Pseudotimeanalysis of genes differentially expressed (DE) along this axis identified thetranscriptional repressor histone deacetylase 4 (HDAC4) as an upstreamregulator of disease progression. HDAC4 wasmislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressedgenes early in the disease axis, leading to latedeficits in protein homeostasis. Treatment of iPSC-derived dopamine neuronswith HDAC4-modulating compounds upregulated genes early in the DE axis andcorrected PD-related cellular phenotypes. Our study demonstrates howsingle-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
参考文献：
Langet al (2019). Single-Cell Sequencing of iPSC-Dopamine Neurons ReconstructsDisease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes. Cell Stem Cell. 2019 Jan 3;24(1):93-106.e6.
9. Neuron—研究发现Aβ斑块可促进α-synuclein播散，而后者可进一步加剧tau蛋白病理、认知和运动功能损害
点评：先前研究发现了阿尔茨海默病和帕金森病痴呆患者的大脑中存在Aβ斑块、tau缠结和α-synuclein病理的共存现象，但人们对这三种病理蛋白是如何相互影响以及如何影响患者的认知和运动表型的仍旧知之甚少。本研究的研究人员将α-synuclein预成型纤维注射入含有丰富Aβ斑块的AD小鼠脑内，然后发现Aβ斑块可以显著地加剧α-synuclein病理的扩散。此外，他们还发现α-synuclein预成型纤维注射入5xFAD小鼠脑内可显著地增加过度磷酸化的tau蛋白，并引起神经元进一步丢失和认知及运动功能的损害。
英文摘要：
Studieshave shown an overlap of Aβ plaques, tau tangles, and α-synuclein(α-syn) pathologies in the brains of Alzheimer's disease(AD) and Parkinson's disease (PD) with dementia(PDD) patients, with increased pathological burden correlating with severity ofcognitive and motor symptoms. Despite the observed co-pathology andconcomitance of motor and cognitive phenotypes, the consequences of the primaryamyloidogenic protein on the secondary pathologies remain poorly understood. Tobetter define the relationship between α-syn and Aβ plaques, we injected α-synpreformed fibrils (α-syn mpffs) into mice with abundant Aβ plaques. Aβ depositsdramatically accelerated α-syn pathogenesis and spread throughout the brain.Remarkably, hyperphosphorylated tau (p-tau) was induced in α-syn mpff-injected5xFAD mice. Finally, α-syn mpff-injected 5xFAD miceshowed neuron loss that correlated with the progressive decline of cognitiveand motor performance. Our findings suggest a "feed-forward"mechanism whereby Aβ plaques enhance endogenous α-syn seeding and spreadingover time post-injection with mpffs.
参考文献:
Bassilet al (2019). Amyloid-Beta (Aβ) Plaques Promote Seeding and Spreading ofAlpha-Synuclein and Tau in a Mouse Model of Lewy Body Disorders with Aβ Pathology. Neuron. 2019 Nov 7.
10. Nature neurosci—动物实验证明不同种类的α-synuclein可诱导不同的神经变性疾病
点评：帕金森病和多系统萎缩都是α-突触核蛋白病，但是这两种疾病却有不同的临床表型和病理表型。在本项研究中，研究人员给转基因小鼠（TgM83小鼠）接种了不同种类的α-synuclein聚集物，发现小鼠出现了不同的病理表型。这些病理表型包括疾病的症状、发病时间、脑内α-synuclein聚集物的形态及其构象、靶细胞类型。这项研究进一步揭示了α-synuclein存在prion样的扩散特性，以及不同的α-synuclein品系如何引起不同的神经变性疾病。
英文摘要：
Theclinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy havebeen postulated to stem from unique strains of α-synuclein aggregates, akin towhat occurs in prion diseases. Here we demonstrate that inoculation oftransgenic mice with different strains of recombinant or brain-derivedα-synuclein aggregates produces clinically and pathologically distinctdiseases. Strain-specific differences were observed in the signs ofneurological illness, time to disease onset,morphology of cerebral α-synuclein deposits and the conformational propertiesof the induced aggregates. Moreover, different strains targeted distinctcellular populations and cell types within the brain, recapitulating theselective targeting observed among human synucleinopathies. Strain-specificclinical, pathological and biochemical differences were faithfully maintainedafter serial passaging, which implies that α-synuclein propagates viaprion-like conformational templating. Thus, pathogenic α-synuclein exhibits keyhallmarks of prion strains, which provides evidence that diseaseheterogeneity among the synucleinopathies is caused by distinct α-synucleinstrains.
参考文献:
Lauet al (2019). α-Synuclein strains targetdistinct brain regions and cell types. Nat Neurosci. 2019 Dec 2.
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20个神经科学领域的突破可能获得诺贝尔奖
1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。
2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；
3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。
4. 睡眠和睡眠障碍的机制和干预研究。
5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。
6. 计算和逻辑推理的神经科学基础研究。
7. 语言的神经科学基础研究。
8. 视觉图像形成和运用的神经科学基础研究。
9. 创造力、想象力和艺术文学创造的神经基础研究。
10. 痛觉的神经科学基础及其干预研究
11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。
12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。
13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；
14. 运动神经元病等神经变性病机制研究及其干预。
15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。
16. 神经系统遗传病的机制研究及基因治疗。
17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。
18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。
19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。
20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。
https://blog.sciencenet.cn/blog-661795-1211700.html
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