2017年帕金森病十大研究进展

2017 年帕金森病十大研究进展2017 年帕金森病十大研究进展中T 细胞免第一位：N atu re 报道 a -synuclein 可能是引起PD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 recognize a -synuclein peptides.Nature. 2017Jun29;546(7660):656-661. AbstractGenetic 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 -synuclein,aa protein aggregated in Parkinson'sdisease, act as antigenic epitopes displayed by these alleles and drivehelper and cytotoxic Tcell 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. 2017Oct7;390(10103):1664-1675.AbstractBACKGROUND: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 moderateParkinson'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's disease as measured by Queen Square Brain Bankcriteria, were on dopaminergic treatment with wearing-off effects, and were atHoehn and Yahr stage 25 or less when on treatment.Randomisation was byweb-based randomisation with a two strata block design according to disease severity. Patients and investigatorswere masked to treatment allocation. The primary outcome was the adjusteddifference in the Movement DisordersSociety 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 at(NCT01971242)and is completed.FINDINGS:Between June 18, 2014, and March 13, 2015, 62 patients wereenrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primaryanalysis included 31 patients in the exenatide group and 29 patients in theplacebo group. At 60 weeks, off-medication scores on part 3 of theMDS-U PDRShad imp roved by 1 Op oints (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 inParkinson'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'sResearch. 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 aprimateParkinson's disease model.Nature. 2017 Aug 30;548(7669):592-596.AbstractInduced pluripotent stem cells (iPS cells) are apromising source for a cell-based therapy to treatParkinson'sdisease (PD), in which midbrain dopaminergic neurons progressivelydegenerate. However, long-term analysis of human iPScell-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。