2018年帕金森病十大研究突破

一.   《Science》：肿瘤相关的酶—腺苷二磷酸核糖（ADP-ribose）聚合酶1是帕金森病的重要致病因子。

本研究的主要发现是PARP-1及其产物PAR可以加剧α-synuclein的病理改变，提示PARP-1是PD的潜在治疗靶点。

摘要：The pathologic accumulation andaggregation of α-synuclein (α-syn) underlies Parkinson's disease (PD).The molecular mechanisms by which pathologic α-syn causes neurodegeneration inPD are not known. Here, we found that pathologic α-syn activates poly(adenosine5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generationaccelerates the formation of pathologic α-syn, resulting in celldeathvia parthanatos. PARP inhibitors or genetic deletion of PARP-1 preventedpathologic α-syn toxicity. In a feed-forward loop, PAR converted pathologicα-syn to a more toxic strain. PAR levels were increased in the cerebrospinalfluid and brains of patients with PD, suggesting that PARP activation plays arole in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activationcould hold promise as a disease-modifying therapy to prevent the loss ofdopamine neurons in PD.

参考文献：Poly(ADP-ribose) drives pathologicα-synuclein neurodegeneration in Parkinson's disease. Science. 2018 Nov2;362(6414). pii: eaat8407.

二.   《Nature》：发现Parkin和PINK1具有抑制神经炎症的作用。

本研究的主要发现是揭示了Parkin和PINK1的与抑制炎症相关的生理功能。代谢应激可以增加线粒体DNA（MtDNA）的损伤，而MtDNA可以引起DNA识别信号通路的激活，后者由cGAS-STING信号通路介导，通过敲除STING可以改善PD模型的病理和运动表型。

摘要：Although serum from patients with Parkinson'sdisease contains elevated levels of numerous pro-inflammatory cytokinesincluding IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or isa consequence of neuronal loss remains unknown¹. Mutations in parkin,an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onsetParkinson's disease^2,3. Both PINK1 and parkin function within the same biochemicalpathway and remove damaged mitochondria from cells in culture and in animalmodels via mitophagy, a selective form of autophagy⁴. The in vivorole of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin haveno substantial Parkinson's-disease-relevant phenotypes^5-7.Mitochondrial stress can lead to the release of damage-associated molecularpatterns (DAMPs) that can activate innate immunity^8-12, suggestingthat mitophagy may mitigate inflammation. Here we report a strong inflammatoryphenotype in both Prkn^-/- and Pink1^-/- mice following exhaustive exercise andin Prkn^-/-;mutator mice, which accumulate mutations in mitochondrialDNA (mtDNA)^13,14. Inflammation resulting from either exhaustiveexercise or mtDNA mutation is completely rescued by concurrent loss of STING, acentral regulator of the type I interferon response to cytosolic DNA^15,16.The loss of dopaminergic neurons from the substantia nigra pars compacta andthe motor defect observed in aged Prkn^-/-;mutator mice are alsorescued by loss of STING, suggesting that inflammation facilitates thisphenotype. Humans with mono- and biallelic PRKN mutations also display elevatedcytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innateimmunity.

参考文献：Parkin and PINK1 mitigate STING-inducedinflammation. Nature. 2018Sep;561(7722):258-262.

三.   《Nature medicine》：阻断A1型星形胶质细胞可以改善PD的运动和病理表型。

本研究主要发现了GLP1R激动剂，NLY01可以防止A1型星形胶质细胞对多巴胺能神经元产生的神经毒性。提示阻断A1型星形胶质细胞的转变是PD的潜在治疗靶点。

摘要：Activation of microglia by classical inflammatorymediators can convert astrocytes into a neurotoxic A1 phenotype in a variety ofneurological diseases^1,2. Development of agents that could inhibitthe formation of A1 reactive astrocytes could be used to treat these diseasesfor which there are no disease-modifying therapies. Glucagon-like peptide-1receptor (GLP1R) agonists have been indicated as potential neuroprotectiveagents for neurologic disorders such as Alzheimer's disease and Parkinson's disease^3-13. The mechanisms bywhich GLP1R agonists are neuroprotective are not known. Here we show that apotent, brain-penetrantlong-acting GLP1R agonist, NLY01, protects against the loss of dopaminergicneurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF)mouse model of sporadic Parkinson's disease^14,15. NLY01 also prolongsthe life and reduces the behavioral deficits and neuropathologicalabnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model ofα-synucleinopathy-induced neurodegeneration¹⁶. We found that NLY01is a potent GLP1R agonist with favorable properties that is neuroprotectivethrough the direct prevention of microglial-mediated conversion of astrocytesto an A1 neurotoxic phenotype. In light of its favorable properties, NLY01should be evaluated in the treatment of Parkinson's disease andrelated neurologic disorders characterized by microglial activation.

参考文献：Block of A1 astrocyte conversion by microgliais neuroprotective in models of Parkinson's disease.Nat Med. 2018Jul;24(7):931-938.

四.   《Cell stem cell》： Th17细胞可以引起PD-iPSC细胞来源的中脑神经元的死亡。

本研究主要的模型是散发性PD来源iPSC衍生来的中脑神经元。主要发现是毒性Th细胞亚型Th17细胞通过IL-17进而损伤PD来源iPSC衍生来的中脑神经元，提示Th17细胞产生的IL-17可以作为PD的潜在治疗靶点。

摘要：Parkinson's disease (PD) is aneurodegenerative disorder characterized by the progressive degeneration ofmidbrain neurons (MBNs). Recent evidence suggests contribution of the adaptiveimmune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotentstem cell (iPSC)-derived MBNs in sporadic PD.Higher Th17 frequencies were found in the blood of PD patients and increasednumbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding usingautologous co-cultures of activated T lymphocytes and iPSC-derived MBNs ofsporadic PD patients and controls. After co-culture with T lymphocytes or theaddition of IL-17, PD iPSC-derived MBNs underwent increased neuronal deathdriven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockageof IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody,secukinumab, rescued the neuronal death. Our findings indicate a critical rolefor IL-17-producing T lymphocytes in sporadic PD.

参考文献：Th17 Lymphocytes Induce Neuronal CellDeath in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell. 2018 Jul 5;23(1):123-131.

五.   《Sci Transl Med》：基因治疗通过重塑脑功能连接进而减轻帕金森病的运动症状。

本项研究是一项II期临床研究，以影像学作为辅助监测手段，主要发现是GAD基因治疗可以在大脑中形成多突触功能通路的代谢影像学特征，这一通路从STN连接到运动区域。研究人员将这一特征性的影像学通路特征称为GAD-related pattern (GADRP)，而这一特征的重要价值在于其和患者的临床改善密切相关。

摘要：Gene therapy is emerging as a promising approach for treatingneurological disorders, including Parkinson's disease (PD).A phase 2 clinical trial showed that delivering glutamic acid decarboxylase (GAD)into the subthalamic nucleus (STN) of patients with PD had therapeutic effects.To determine the mechanism underlying this response, we analyzed metabolicimaging data from patients who received gene therapy and those randomized tosham surgery, all of whom had been scanned preoperatively and at 6 and 12months after surgery. Those who received GAD gene therapy developed a uniquetreatment-dependent polysynaptic brain circuitthat we termed as the GAD-relatedpattern (GADRP), which reflected the formation of new polysynaptic functionalpathways linking the STN to motor cortical regions. Patients in both thetreatment group and the sham group expressed the previously reported placebonetwork (the sham surgery-related pattern or SSRP) when blinded to thetreatment received. However, only the appearance of the GADRP correlated withclinical improvement in the gene therapy-treated subjects. Treatment-induced brain circuits can thus be useful inclinical trials for isolating true treatment responses and providing insightinto their underlying biological mechanisms.

参考文献：Gene therapy reduces Parkinson's diseasesymptoms by reorganizing functional brain connectivity. Sci Transl Med. 2018Nov 28;10(469). pii: eaau0713.

六.   《Cell》：报道TAF1是引起X连锁肌张力障碍-帕金森综合征的致病位点。

X连锁肌张力障碍-帕金森综合征是孟德尔遗传性神经变性疾病。本研究的主要发现是SINE-VNTR-Alu (SVA)介导的TAF1的异常转录引起X连锁肌张力障碍-帕金森综合征。

摘要：X-linked Dystonia-Parkinsonism (XDP) is aMendelian neurodegenerative disease thatis endemic to the Philippines and is associated with a founder haplotype. Weintegrated multiple genome and transcriptome assembly technologies to narrowthe causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA)retrotransposition into intron 32 of the gene. Transcriptome analysesidentified decreased expression of the canonical cTAF1 transcript among XDP probands,and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1transcription that involved alternative splicing and intron retention (IR) inproximity to the SVA that was anti-correlated with overall TAF1 expression.CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptionalsignature and normalized TAF1 expression in probands. These data suggest anSVA-mediated aberrant transcriptional mechanism associated with XDP and mayprovide a roadmap for layered technologies and integrated assembly-basedanalyses for other unsolved Mendelian disorders.

参考文献：Dissecting the Causal Mechanism ofX-Linked Dystonia-Parkinsonism by Integrating Genome and TranscriptomeAssembly. Cell. 2018 Feb 22;172(5):897-909.e21.

七.    《Cell stem cell》：单细胞测序发现HDAC4是帕金森病细胞病理表型的重要调节因子。

本研究使用的细胞模型是GBA-N370S携带PD患者来源iPSC分化的多巴胺能神经元，主要方法是单细胞转录组测序。主要发现是HDAC4是PD多巴胺能神经元损伤的重要调节因子。主要研究意义是揭示了单细胞测序在揭示PD致病机制的异质性和发现治疗靶点中的价值。

摘要：Induced pluripotentstem cell (iPSC)-derived dopamine neurons provide an opportunity to modelParkinson's disease (PD), but neuronal cultures are confounded by asynchronousand heterogeneous appearance of disease phenotypes in vitro. Usinghigh-resolution, single-cell transcriptomic analyses of iPSC-derived dopamineneurons carrying the GBA-N370S PD risk variant, we identified a progressiveaxis of gene expression variation leading to endoplasmic reticulum stress.Pseudotime analysis of genes differentially expressed (DE) along this axisidentified the transcriptional repressor histone deacetylase 4 (HDAC4) as anupstream regulator of disease progression. HDAC4 was mislocalized to thenucleus in PD iPSC-derived dopamine neurons and repressed genes early in thedisease axis, leading to late deficits in protein homeostasis. Treatment ofiPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genesearly in the DE axis and corrected PD-related cellular phenotypes. Our studydemonstrates how single-cell transcriptomics can exploit cellular heterogeneityto reveal disease mechanisms and identify therapeutic targets.

参考文献：Single-CellSequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression andIdentifies HDAC4 as a Regulator of Parkinson Cell Phenotypes. Cell Stem Cell. 2018 Nov 20. pii:S1934-5909(18)30504-6. 

八.   《Sci Transl Med》：研究发现切除阑尾可以降低帕金森病的发生风险。

两项独立的流行病学研究发现阑尾移除可以降低PD的发生风险，并延迟PD的起病年龄。研究人员认为可能是因为阑尾中含有病理性α-synuclein蛋白。

摘要：The pathogenesis of Parkinson'sdisease (PD) involves theaccumulation of aggregated α-synuclein, which has been suggested to begin inthe gastrointestinal tract. Here, we determined the capacity of the appendix tomodify PD risk and influence pathogenesis. In two independent epidemiologicaldatasets, involving more than 1.6 million individuals and over 91 millionperson-years, we observed that removal of the appendix decades before PD onsetwas associated with a lower risk for PD, particularly for individuals living inrural areas, and delayed the age of PD onset. We also found that the healthyhuman appendix contained intraneuronal α-synuclein aggregates and an abundanceof PD pathology-associated α-synuclein truncation products that are known toaccumulate in Lewy bodies, the pathological hallmark of PD. Lysates of humanappendix tissue induced the rapid cleavage and oligomerization of full-lengthrecombinant α-synuclein. Together, we propose that the normal human appendixcontains pathogenic forms of α-synuclein that affect the risk of developing PD.

参考文献：The vermiform appendix impacts the risk of developing Parkinson'sdisease. Sci Transl Med. 2018 Oct 31;10(465). pii: eaar5280.

九.   《Neuron》：阻断α-synuclein四聚体引起类似于PD的多巴反应性运动综合征。

本研究主要揭示了PD相关的突变E46K如何引起四聚体向单体的转变，而后者可以异常聚集形成α-synuclein多聚体。E46K引起的这种构像的改变可以引起突变小鼠运动功能损害和中脑黑质多巴胺能神经元的丢失。

摘要：α-Synuclein (αS) regulates vesicleexocytosis but forms insoluble deposits in Parkinson's disease (PD).Developing disease-modifyingtherapies requires animal models that reproduce cardinal features of PD. Werecently described a previously unrecognized physiological form of αS,α-helical tetramers, and showed that familial PD-causing missense mutationsshift tetramers to aggregation-prone monomers. Here, we generated miceexpressing the fPD E46K mutation plus 2 homologous E→K mutations inadjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypessimilar to PD. αS monomers accumulate at membranes and form vesicle-richinclusions. αS becomes insoluble, proteinase K-resistant,Ser129-phosphorylated, and C-terminally truncated, as in PD. These changesaffect regions controlling motor behavior, including a decrease innigrostriatal dopaminergic neurons. The outcome is a progressive motor syndromeincluding tremor and gait and limb deficits partially responsive to L-DOPA.This fully penetrant phenotype indicates that tetramers are required for normalαS homeostasis and that chronically shifting tetramers to monomers may resultin PD, with attendant therapeutic implications.

参考文献：Abrogating Nativeα-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome CloselyResembling Parkinson's Disease. Neuron. 2018 Oct 10;100(1):75-90.e5.

十.   《Neuron》：糖基化神经酰胺可以将α-synuclein转变为毒性多聚体。

葡糖脑苷脂酶（GBA1）突变是引起PD的重要遗传变异。GBA1突变引起糖基化鞘磷脂（GCLs），如糖基化神经酰胺的清除障碍。本研究的主要发现是揭示了糖基化神经酰胺的沉积可以引起α-synuclein向毒性多聚体的转变，这可能是PD的重要致病机制和潜在的干预靶点。

摘要：α-Synuclein (α-syn) aggregation is a key event inParkinson's disease (PD). Mutations in glycosphingolipid (GSL)-degradingglucocerebrosidase are risk factors for PD, indicating that disrupted GSLclearance plays a key role in α-syn aggregation. However, the mechanisms ofGSL-induced aggregation are not completely understood. We document the presenceof physiological α-syn conformers in human midbrain dopamine neurons and testedtheir contribution to the aggregation process. Pathological α-syn assemblymainly occurred through the conversion of high molecular weight (HMW)physiological α-syn conformers into compact, assembly-state intermediates byglucosylceramide (GluCer), without apparent disassembly into free monomers.This process was reversible in vitro through GluCer depletion. ReducingGSLs in PD patient neurons with and without GBA1 mutations diminished pathologyand restored physiological α-syn conformers that associated with synapses. Ourwork indicates that GSLs control the toxic conversion of physiological α-synconformers in a reversible manner that is amenable to therapeutic interventionby GSL reducing agents.

参考文献：Reversible Conformational Conversion ofα-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018 Jan 3;97(1):92-107.e10. 

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