Lerche Stefanie, Sjödin Simon, Brinkmalm Ann, Blennow Kaj, Wurster Isabel, Roeben Benjamin, Zimmermann Milan, Hauser Ann-Kathrin, Liepelt-Scarfone Inga, Waniek Katharina, Lachmann Ingolf, Gasser Thomas, Zetterberg Henrik, Brockmann Kathrin
Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany.
Mov Disord. 2021 Nov;36(11):2595-2604. doi: 10.1002/mds.28704. Epub 2021 Jun 28.
Molecular pathways associated with α-synuclein proteostasis have been detected in genetic studies and in cell models and include autophagy, ubiquitin-proteasome system, mitochondrial homeostasis, and synaptic plasticity. However, we lack biomarkers that are representative for these pathways in human biofluids.
The objective of this study was to evaluate CSF protein profiles of pathways related to α-synuclein proteostasis.
We assessed CSF protein profiles associated with neurotransmitter secretion, synapse plasticity, and autophagy in 2 monocentric cohorts with α-synucleinopathy (385 PD patients and 67 DLB patients). We included 80 PD patients and 17 DLB patients with variants in the glucocerebrosidase gene to serve as proxy for accelerated α-synuclein pathology with pronounced clinical trajectories.
(1) Proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy were lower in PD and DLB patients compared with healthy controls. (2) These patterns were more pronounced in DLB than in PD patients, accentuated by GBA variant status in both entities. (3) CSF levels of these proteins were positively associated with CSF levels of total α-synuclein, with lower levels of proteostasis proteins related to lower levels of total α-synuclein. (4) These findings could be confirmed longitudinally. PD patients with low CSF profiles of proteostasis proteins showed lower CSF levels of α-synuclein longitudinally compared with PD patients with a normal proteostasis profile.
CSF proteins associated with neurotransmitter secretion, synaptic plasticity, and endolysosomal autophagy might serve as biomarkers related to α-synuclein proteostasis in PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
在基因研究和细胞模型中已检测到与α-突触核蛋白蛋白质稳态相关的分子途径，包括自噬、泛素-蛋白酶体系统、线粒体稳态和突触可塑性。然而，我们缺乏在人体生物流体中代表这些途径的生物标志物。
本研究的目的是评估与α-突触核蛋白蛋白质稳态相关途径的脑脊液蛋白质谱。
我们在2个单中心队列中评估了与神经递质分泌、突触可塑性和自噬相关的脑脊液蛋白质谱，这些队列中的患者患有α-突触核蛋白病（385例帕金森病患者和67例路易体痴呆患者）。我们纳入了80例帕金森病患者和17例路易体痴呆患者，这些患者的葡萄糖脑苷脂酶基因存在变异，以作为具有明显临床病程的加速α-突触核蛋白病理的替代指标。
（1）与健康对照相比，帕金森病和路易体痴呆患者中与神经递质分泌、突触可塑性和内溶酶体自噬相关的蛋白质水平较低。（2）这些模式在路易体痴呆患者中比在帕金森病患者中更明显，在两个队列中均因GBA变异状态而加剧。（3）这些蛋白质的脑脊液水平与总α-突触核蛋白的脑脊液水平呈正相关，蛋白质稳态水平较低与总α-突触核蛋白水平较低相关。（4）这些发现可以纵向得到证实。与蛋白质稳态谱正常的帕金森病患者相比，蛋白质稳态蛋白脑脊液谱低的帕金森病患者纵向脑脊液α-突触核蛋白水平较低。
与神经递质分泌、突触可塑性和内溶酶体自噬相关的脑脊液蛋白可能作为帕金森病和路易体痴呆中与α-突触核蛋白蛋白质稳态相关的生物标志物。© 2021作者。《运动障碍》由Wiley Periodicals LLC代表国际帕金森和运动障碍协会出版。
