2017年帕金森病十大研究进展

第一位：Nature报道α-synuclein可能是引起PD中T细胞免疫异常的关键抗原，提示PD的发生可能与自身免疫机制相关。

Sulzer et al. T cells from patients with Parkinson'sdisease recognizeα-synuclein peptides.Nature. 2017 Jun29;546(7660):656-661.

Abstract

Genetic studies have shown the association of Parkinson'sdisease with alleles ofthe major histocompatibility complex. Here we show that a defined set ofpeptides that are derived from α-synuclein, a protein aggregated in Parkinson'sdisease, act as antigenic epitopes displayed by these alleles and drivehelper and cytotoxic T cell responsesin patients with Parkinson's disease. These responses may explain theassociation of Parkinson's disease withspecific major histocompatibility complex alleles.

第二位：Lancet临床试验证实糖尿病治疗药物Exenatide（GLP-1激动剂）可以用于治疗帕金森病

Athauda et al. Exenatide once weekly versus placebo in Parkinson'sdisease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Oct7;390(10103):1664-1675.

Abstract

BACKGROUND:

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, hasneuroprotective effects in preclinical models of Parkinson'sdisease. We investigated whether these effects would be apparent in aclinical trial.

METHODS:

In this single-centre, randomised, double-blind,placebo-controlled trial, patients with moderate Parkinson'sdisease were randomlyassigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placeboonce weekly for 48 weeks in addition to their regular medication, followed by a12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson'sdisease as measured byQueen Square Brain Bank criteria, were on dopaminergic treatment withwearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when ontreatment. Randomisation was by web-based randomisation with a two strata blockdesign according to disease severity.Patients and investigators were masked to treatment allocation. The primaryoutcome was the adjusted difference in the Movement Disorders Society Unified Parkinson'sDisease Rating Scale(MDS-UPDRS) motor subscale (part 3) in the practically defined off-medicationstate at 60 weeks. All efficacy analyses were based on a modifiedintention-to-treat principle, which included all patients who completed anypost-randomisation follow-up assessments. The study is registered atClinicalTrials.gov (NCT01971242)and is completed.

FINDINGS:

Between June 18, 2014, and March 13, 2015, 62 patients were enrolledand randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysisincluded 31 patients in the exenatide group and 29 patients in the placebogroup. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS hadimproved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsenedby 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean differenceof -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions andgastrointestinal symptoms were common adverse events in both groups. Sixserious adverse events occurred in the exenatide group and two in the placebogroup, although none in either group were judged to be related to the studyinterventions.

INTERPRETATION:

Exenatide had positive effects on practically definedoff-medication motor scores in Parkinson's disease, which were sustained beyond theperiod of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induceslong-lasting symptomatic effects is uncertain. Exenatide represents a major newavenue for investigation in Parkinson's disease, and effects on everyday symptomsshould be examined in longer-term trials.

FUNDING:

Michael J Fox Foundation for Parkinson's Research.

第三位：人类iPSC来源的多巴胺能神经元移植首次在灵长类动物中获得成功。

Kikuchi et al. HumaniPS cell-derived dopaminergic neurons function in aprimate Parkinson's disease model.Nature. 2017 Aug 30;548(7669):592-596.

Abstract

Induced pluripotent stem cells (iPS cells) are apromising source for a cell-based therapy to treat Parkinson'sdisease (PD), in which midbrain dopaminergic neurons progressivelydegenerate. However, long-term analysis of human iPS cell-deriveddopaminergic neurons in primate PD models has never been performed to ourknowledge. Here we show that human iPS cell-derived dopaminergicprogenitor cells survived and functioned as midbrain dopaminergic neurons in aprimate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-basedand video-recording analyses revealed an increase in spontaneous movement ofthe monkeys after transplantation. Histological studies showed that the maturedopaminergic neurons extended dense neurites into the host striatum; thiseffect was consistent regardless of whether the cells were derived frompatients with PD or from healthy individuals. Cells sorted by the floor platemarker CORIN did not form any tumours in the brains for at least two years.Finally, magnetic resonance imaging and positron emission tomography were usedto monitor the survival, expansion and function of the grafted cells as well asthe immune response in the host brain. Thus, this preclinical study using aprimate model indicates that human iPS cell-derived dopaminergic progenitorsare clinically applicable for the treatment of patients with PD.

第四位：Science研究揭示了多巴胺氧化在耦联线粒体和溶酶体功能障碍中的关键作用，提示氧化应激可能是引起多巴胺能神经元变性的起始步骤。

Burbulla et al.Dopamine oxidation mediates mitochondrial and lysosomal dysfunctionin Parkinson's disease.Science. 2017 Sep 22;357(6357):1255-1261.

Abstract

Mitochondrial and lysosomal dysfunction have beenimplicated in substantia nigra dopaminergic neurodegeneration in Parkinson'sdisease (PD), but how these pathways are linked in human neurons remainsunclear. Here we studied dopaminergic neurons derived from patients withidiopathic and familial PD. We identified a time-dependent pathological cascadebeginning with mitochondrial oxidant stress leading to oxidized dopamineaccumulation and ultimately resulting in reduced glucocerebrosidase enzymaticactivity, lysosomal dysfunction, and α-synuclein accumulation. This toxiccascade was observed in human, but not in mouse, PD neurons at least in partbecause of species-specific differences in dopamine metabolism. Increasingdopamine synthesis or α-synuclein amounts in mouse midbrain neuronsrecapitulated pathological phenotypes observed in human neurons. Thus, dopamineoxidation represents an important link between mitochondrial and lysosomaldysfunction in PD pathogenesis.

第五位：Science研究报道了β2-肾上腺素受体是α-synuclein基因转录的调节因子并且和PD的发生风险密切相关。

Mittal et al.β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson'sdisease.Science. 2017 Sep 1;357(6354):891-898.

Abstract

Copy number mutations implicate excess production ofα-synuclein as a possibly causative factor in Parkinson'sdisease (PD). Using an unbiased screen targeting endogenous geneexpression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator ofthe α-synuclein gene (SNCA). β2AR ligands modulate SNCA transcriptionthrough histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11years of follow-up in 4 million Norwegians, the β2AR agonist salbutamol, abrain-penetrant asthma medication, was associated with reduced risk ofdeveloping PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76).Conversely, a β2AR antagonist correlated with increased risk. β2AR activationprotected model mice and patient-derived cells. Thus, β2AR  is linked to transcription of α-synuclein and risk of PD in aligand-specific fashion and constitutes a potential target for therapies.

第六位：Cell StemCell研究鉴定出hESC移植治疗PD的预后预测标志物，这为将来判断移植后治疗预后提供了参考依据。

Kirkeby et al. Predictive Markers Guide Differentiation to ImproveGraft Outcome in Clinical Translation of hESC-Based Therapyfor Parkinson's Disease.CellStem Cell. 2017 Jan 5;20(1):135-148.

Abstract

Stem cell treatments for neurodegenerativediseases are expected to reach clinical trials soon. Most of the approachescurrently under development involve transplantation of immature progenitorsthat subsequently undergo phenotypic and functional maturation in vivo,and predicting the long-term graft outcome already at the progenitor stageremains a challenge. Here, we took an unbiased approach to identify predictivemarkers expressed in dopamine neuron progenitors that correlate withgraft outcome in an animal model of Parkinson's disease through geneexpression analysis of >30 batches of grafted human embryonicstem cell (hESC)-derived progenitors. We found that many of thecommonly used markers did not accurately predict in vivo subtype-specificmaturation. Instead, we identified a specific set of markers associatedwith the caudal midbrain that correlate with high dopaminergicyield after transplantation in vivo. Using these markers,we developed a good manufacturing practice (GMP) differentiation protocolfor highly efficient and reproducible production of transplantable dopamineprogenitors from hESCs.

第七位：Nature研究报道星型胶质细胞亚群A1可能在中枢神经系统变性病的发生中扮演重要角色。

Liddelow et al.Neurotoxic reactive astrocytes are induced by activated microglia.Nature. 2017 Jan 26;541(7638):481-487.

Abstract

Reactive astrocytes are strongly induced by centralnervous system (CNS) injury and disease, but their role is poorlyunderstood. Here we show that a subtype of reactive astrocytes, which we termedA1, is induced by classically activated neuroinflammatory microglia. We showthat activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q,and that these cytokines together are necessary and sufficient to induce A1astrocytes. A1 astrocytes lose the ability to promote neuronal survival,outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons andoligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when theformation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes areabundant in various human neurodegenerative diseases including Alzheimer's,Huntington's and Parkinson's disease, amyotrophic lateral sclerosis andmultiple sclerosis. Taken together these findings help to explain why CNSneurons die after axotomy, strongly suggest that A1 astrocytes contribute tothe death of neurons and oligodendrocytes in neurodegenerative disorders, andprovide opportunities for the development of new treatments for these diseases.

第八位：Nature neuroscience研究揭示了多巴胺能神经元在PD中发生特异性变性的一种可能机制。

Mor et al.Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.Nat Neurosci. 2017 Nov;20(11):1560-1568.

Abstract

Parkinson's disease (PD) is defined by the loss ofdopaminergic neurons in the substantia nigra and the formation of Lewy bodyinclusions containing aggregated α-synuclein. Efforts to explaindopamine neuron vulnerability are hindered by the lack of dopaminergic cell deathin α-synuclein transgenic mice. To address this, we manipulated both dopaminelevels and α-synuclein expression. Nigrally targeted expression of mutanttyrosine hydroxylase with enhanced catalytic activity increased dopamine levelswithout damaging neurons in non-transgenic mice. In contrast, raising dopaminelevels in mice expressing human A53T mutant α-synuclein induced progressivenigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53Tmice increased levels of potentially toxic α-synuclein oligomers, resulting inconformationally and functionally modified species. Moreover, in geneticallytractable Caenorhabditis elegans models, expression of α-synuclein mutated atthe site of interaction with dopamine prevented dopamine-induced toxicity.These data suggest that a unique mechanism links two cardinal features of PD:dopaminergic cell death and α-synuclein aggregation.

第九位：Neuron研究揭示了LRRK2缺失引起PD神经变性和自噬-溶酶体异常的机制。

Giaime et al. Age-Dependent DopaminergicNeurodegeneration and Impairment of the Autophagy-Lysosomal Pathway inLRRK-Deficient Mice.Neuron. 2017 Nov 15;96(4):796-807.e6.

Abstract

LRRK2 mutations are the most common genetic cause of Parkinson'sdisease, but LRRK2's normal physiological role in the brain is unclear. Here,we show that inactivation of LRRK2 and its functional homolog LRRK1 results inearlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic(DA) neurons in the substantia nigra pars compacta (SNpc) and of noradrenergicneurons in the locus coeruleus is accompanied with increases in apoptosis,whereas the cerebral cortex and cerebellum are unaffected. Furthermore,selective age-dependent neurodegeneration is only present in LRRK-/-,not LRRK1-/- or LRRK2-/- brains, and it isaccompanied by increases in α-synuclein and impairment of theautophagy-lysosomal pathway. Quantitative electron microscopy (EM) analysisrevealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK-/- micebefore the onset of DA neuronloss. These findings revealed an essentialrole of LRRK in the survival of DA neurons and in the regulation of theautophagy-lysosomal pathway in the aging brain.

第十位：Science研究揭示α-synuclein破坏细胞膜和损害细胞功能的结构学基础，这为开发以α-synuclein的构象为靶点的药物奠定了坚实的基础。

Fusco et al.Structural basis of membrane disruption and cellular toxicity by α-synucleinoligomers.Science. 2017 Dec 15;358(6369):1440-1443.

Abstract

Oligomeric species populated during the aggregationprocess of α-synuclein have been linked to neuronal impairment in Parkinson'sdisease and related neurodegenerative disorders. By using solution andsolid-state nuclear magnetic resonance techniques in conjunction with otherstructural methods, we identified the fundamental characteristics that enabletoxic α-synuclein oligomers to perturb biological membranes and disruptcellular function; these include a highly lipophilic element that promotesstrong membrane interactions and a structured region that inserts into lipidbilayers and disrupts their integrity. In support of these conclusions,mutations that target the region that promotes strong membrane interactions byα-synuclein oligomers suppressed their toxicity in neuroblastoma cells andprimary cortical neurons.