Bassil Fares, Canron Marie-Hélène, Vital Anne, Bezard Erwan, Li Yazhou, Greig Nigel H, Gulyani Seema, Kapogiannis Dimitrios, Fernagut Pierre-Olivier, Meissner Wassilios G
Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000 Bordeaux, France.
Brain. 2017 May 1;140(5):1420-1436. doi: 10.1093/brain/awx044.
See Stayte and Vissel (doi:10.1093/awx064) for a scientific commentary on this article. Multiple system atrophy is a fatal sporadic adult-onset neurodegenerative disorder with no symptomatic or disease-modifying treatment available. The cytopathological hallmark of multiple system atrophy is the accumulation of α-synuclein aggregates in oligodendrocytes, forming glial cytoplasmic inclusions. Impaired insulin/insulin-like growth factor-1 signalling (IGF-1) and insulin resistance (i.e. decreased insulin/IGF-1) have been reported in other neurodegenerative disorders such as Alzheimer's disease. Increasing evidence also suggests impaired insulin/IGF-1 signalling in multiple system atrophy, as corroborated by increased insulin and IGF-1 plasma concentrations in multiple system atrophy patients and reduced IGF-1 brain levels in a transgenic mouse model of multiple system atrophy. We here tested the hypothesis that multiple system atrophy is associated with brain insulin resistance and showed increased expression of the key downstream messenger insulin receptor substrate-1 phosphorylated at serine residue 312 in neurons and oligodendrocytes in the putamen of patients with multiple system atrophy. Furthermore, the expression of insulin receptor substrate 1 (IRS-1) phosphorylated at serine residue 312 was more apparent in inclusion bearing oligodendrocytes in the putamen. By contrast, it was not different between both groups in the temporal cortex, a less vulnerable structure compared to the putamen. These findings suggest that insulin resistance may occur in multiple system atrophy in regions where the neurodegenerative process is most severe and point to a possible relation between α-synuclein aggregates and insulin resistance. We also observed insulin resistance in the striatum of transgenic multiple system atrophy mice and further demonstrate that the glucagon-like peptide-1 analogue exendin-4, a well-tolerated and Federal Drug Agency-approved antidiabetic drug, has positive effects on insulin resistance and monomeric α-synuclein load in the striatum, as well as survival of nigral dopamine neurons. Additionally, plasma levels of exosomal neural-derived IRS-1 phosphorylated at serine residue 307 (corresponding to serine residue 312 in humans) negatively correlated with survival of nigral dopamine neurons in multiple system atrophy mice treated with exendin-4. This finding suggests the potential for developing this peripheral biomarker candidate as an objective outcome measure of target engagement for clinical trials with glucagon-like peptide-1 analogues in multiple system atrophy. In conclusion, our observation of brain insulin resistance in multiple system atrophy patients and transgenic mice together with the beneficial effects of the glucagon-like peptide-1 agonist exendin-4 in transgenic mice paves the way for translating this innovative treatment into a clinical trial.
有关本文的科学评论，请参阅斯泰特和维塞尔（doi:10.1093/awx064）。多系统萎缩是一种致命的散发性成人发病的神经退行性疾病，目前尚无对症或改变疾病进程的治疗方法。多系统萎缩的细胞病理学特征是少突胶质细胞中α-突触核蛋白聚集体的积累，形成胶质细胞质包涵体。在阿尔茨海默病等其他神经退行性疾病中，已报道胰岛素/胰岛素样生长因子-1信号传导（IGF-1）受损和胰岛素抵抗（即胰岛素/IGF-1降低）。越来越多的证据还表明多系统萎缩中存在胰岛素/IGF-1信号传导受损，多系统萎缩患者血浆胰岛素和IGF-1浓度升高以及多系统萎缩转基因小鼠模型中IGF-1脑水平降低均证实了这一点。我们在此检验了多系统萎缩与脑胰岛素抵抗相关的假设，并发现多系统萎缩患者壳核中神经元和少突胶质细胞中丝氨酸残基312磷酸化的关键下游信使胰岛素受体底物-1表达增加。此外，丝氨酸残基312磷酸化的胰岛素受体底物1（IRS-1）在壳核中含有包涵体的少突胶质细胞中表达更明显。相比之下，在颞叶皮质中两组之间没有差异，颞叶皮质与壳核相比是一个较不易受影响的结构。这些发现表明胰岛素抵抗可能在神经退行性过程最严重的区域的多系统萎缩中发生，并指出α-突触核蛋白聚集体与胰岛素抵抗之间可能存在关联。我们还在转基因多系统萎缩小鼠的纹状体中观察到胰岛素抵抗，并进一步证明胰高血糖素样肽-1类似物艾塞那肽-4（一种耐受性良好且已获美国食品药品监督管理局批准的抗糖尿病药物）对纹状体中的胰岛素抵抗和单体α-突触核蛋白负荷以及黑质多巴胺神经元的存活具有积极作用。此外，丝氨酸残基307（相当于人类丝氨酸残基312）磷酸化的外泌体神经源性IRS-1的血浆水平与用艾塞那肽-4治疗的多系统萎缩小鼠中黑质多巴胺神经元的存活呈负相关。这一发现表明开发这种外周生物标志物候选物作为多系统萎缩中胰高血糖素样肽-1类似物临床试验中靶点参与的客观结果指标的潜力。总之，我们在多系统萎缩患者和转基因小鼠中观察到脑胰岛素抵抗以及胰高血糖素样肽-1激动剂艾塞那肽-4在转基因小鼠中的有益作用，为将这种创新治疗方法转化为临床试验铺平了道路。
