Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
PLoS Pathog. 2024 Sep 12;20(9):e1012517. doi: 10.1371/journal.ppat.1012517. eCollection 2024 Sep.
The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson's disease. Previously, we generated the "Salt (S)" and "No Salt (NS)" strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC. Following intracerebral inoculation with the S or NS strain, the absence of PrPC in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.
细胞朊病毒蛋白 PrPC 被推测作为α-突触核蛋白的受体发挥作用，可能促进神经退行性疾病（如帕金森病）中α-突触核蛋白聚集物的细胞间传播和/或毒性。此前，我们生成了“盐（S）”和“无盐（NS）”两种α-突触核蛋白聚集物菌株，这些菌株在过表达 A53T 突变型人α-突触核蛋白的 M83 转基因小鼠中引起不同的病理表型。为了检验 PrPC 促进α-突触核蛋白聚集物传播的假说，我们制备了表达或不表达 PrPC 的 M83 小鼠。用 S 或 NS 菌株进行脑内接种后，M83 小鼠中 PrPC 的缺失并未阻止疾病的发展，并且对α-突触核蛋白菌株特异性属性（如大脑中α-突触核蛋白沉积的程度、特定脑区和细胞类型的选择性靶向、诱导的α-突触核蛋白沉积的形态以及抗蛋白酶的α-突触核蛋白聚集物的结构指纹）的影响很小。同样，在 S 菌株腹腔接种后，表达或不表达 PrPC 的 M83 小鼠之间的疾病表现也没有明显差异。有趣的是，用 NS 菌株腹腔接种导致了两种不同的疾病表型，表明α-突触核蛋白菌株的进化，但这也与 PrPC 表达无关。总体而言，这些结果表明，在表达 A53T 突变型人α-突触核蛋白的小鼠中，PrPC 在α-突触核蛋白菌株的传播、神经入侵和进化中最多只起次要作用。因此，其他假定的受体或细胞间传播机制可能对疾病期间α-突触核蛋白聚集物的传播有更大的影响。
