Tavassoly Omid, Del Cid Pellitero Esther, Larroquette Frederique, Cai Eddie, Thomas Rhalena A, Soubannier Vincent, Luo Wen, Durcan Thomas M, Fon Edward A
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
Neurotherapeutics. 2021 Apr;18(2):979-997. doi: 10.1007/s13311-021-01017-6. Epub 2021 Mar 12.
Aggregation and deposition of α-synuclein (α-syn) in Lewy bodies within dopamine neurons of substantia nigra (SN) is the pathological hallmark of Parkinson's disease (PD). These toxic α-syn aggregates are believed to propagate from neuron-to-neuron and spread the α-syn pathology throughout the brain beyond dopamine neurons in a prion-like manner. Targeting propagation of such α-syn aggregates is of high interest but requires identifying pathways involving in this process. Evidence from previous Alzheimer's disease reports suggests that EGFR may be involved in the prion-like propagation and seeding of amyloid-β. We show here that EGFR regulates the uptake of exogenous α-syn-PFFs and the levels of endogenous α-syn in cell cultures and a mouse model of α-syn propagation, respectively. Thus, we tested the therapeutic potentials of AZD3759, a highly selective BBB-penetrating EGFR inhibitor, in a preclinical mouse model of α-syn propagation. AZD3759 decreases activated EGFR levels in the brain and reduces phosphorylated α-synuclein (pSyn) pathology in brain sections, including striatum and SN. As AZD3759 is already in the clinic, this paper's results suggest a possible repositioning of AZD3759 as a disease-modifying approach for PD.
α-突触核蛋白（α-syn）在黑质（SN）多巴胺能神经元的路易小体中聚集和沉积是帕金森病（PD）的病理标志。这些有毒的α-syn聚集体被认为以朊病毒样方式从一个神经元传播到另一个神经元，并将α-syn病理变化扩散到多巴胺能神经元以外的整个大脑。针对这种α-syn聚集体的传播是一个备受关注的问题，但需要确定参与这一过程的途径。先前关于阿尔茨海默病的报道证据表明，表皮生长因子受体（EGFR）可能参与淀粉样β蛋白的朊病毒样传播和播种。我们在此表明，EGFR分别调节细胞培养物和α-syn传播小鼠模型中外源性α-syn原纤维片段（α-syn-PFFs）的摄取和内源性α-syn的水平。因此，我们在α-syn传播的临床前小鼠模型中测试了一种高度选择性的可穿透血脑屏障的EGFR抑制剂AZD3759的治疗潜力。AZD3759可降低大脑中活化的EGFR水平，并减少包括纹状体和黑质在内的脑切片中磷酸化α-突触核蛋白（pSyn）的病理变化。由于AZD3759已进入临床，本文的结果表明AZD3759可能重新定位为一种用于治疗帕金森病的疾病修饰方法。
