Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA1 mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granule cell layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, which might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we performed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dynactin Subunit 2 (Dctn2) interaction was shared across all PFF conditions, and NCK Associated Protein 1 (Nckap1) and Adaptor Related Protein Complex 3 Subunit Beta 2 (Ap3b2) were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

帕金森病 (PD) 是一种神经退行性疾病，其特征是进行性运动症状和神经系统中 α-突触核蛋白 (αsyn) 聚集。由于尚不清楚的原因，具有某些GBA1突变 (GBA-PD) 的 PD 患者具有更积极的临床进展。可以解释这种现象的两个可检验的假设是GBA1突变促进 αsyn 传播或驱动高致病性 αsyn 多态性（即菌株）的产生。我们通过用人类 α-syn 预制原纤维 (PFF) 治疗纯合GBA1 D409V 敲入 (KI) 小鼠，并用从特发性脑病患者收集的脑尸检样本中扩增的几种 αsyn-PFF 多晶型物治疗野生型小鼠 (WT)，测试了这些假设。具有纯合或杂合GBA1突变的 PD 和 GBA-PD 患者。 PFF 注射后六个月，在注射部位（即嗅球颗粒细胞层）和整个大脑观察到强磷酸化-αsyn (PSER129) 阳性病理。无论小鼠基因型或 PFF 多态性如何，PFF 播种效率和传播程度都相似。我们发现，无论患者基因型如何，从人脑中扩增的 PFF 通常比完全合成的 PFF（即非扩增）更有效。然而，这两项研究之间的 PFF 浓度不同，这也可能解释了观察到的差异。为了研究不同接种条件下病理学的分子组成是否存在差异，我们对 PSER129 (BAR-PSER129) 进行了抗体识别生物素化。 我们发现，对于 BAR-PSER129，内源性 PSER129 库主导了已识别的相互作用，因此，对于种子病理学，明确识别出的潜在相互作用非常少。然而，我们发现 Dynactin 亚基 2 (Dctn2) 相互作用在所有 PFF 条件下都是共有的，并且 NCK 相关蛋白 1 (Nckap1) 和接头相关蛋白复合物 3 亚基 Beta 2 (Ap3b2) 是从杂合子 GBA-PD 大脑中扩增的 PFF 所特有的突变携带者。总之，基因型和 αsyn 菌株对总体播种效率和整体 PSER129 相互作用影响不大。