Enomoto Masahiro, Martinez-Valbuena Ivan, Forrest Shelley L, Xu Xiaoxiao, Munhoz Renato P, Li Jun, Rogaeva Ekaterina, Lang Anthony E, Kovacs Gabor G
Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.
Commun Biol. 2025 Jun 16;8(1):929. doi: 10.1038/s42003-025-08355-7.
The ordered assembly of α-synuclein protein encoded by SNCA into filaments characterizes neurodegenerative synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal and multiple system atrophy (MSA), predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that the structures of α-synuclein filaments from LBD differ from MSA and juvenile-onset synucleinopathy (JOS). The rare atypical MSA subtype shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that α-synuclein can form a Lewy-MSA hybrid fold, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs), and conformational stability assays (CSA), are also linked to cytopathological differences. We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds.
由SNCA编码的α-突触核蛋白有序组装成细丝是神经退行性突触核蛋白病的特征。路易体病（LBD）主要表现为神经元病变，而多系统萎缩（MSA）主要表现为少突胶质细胞α-突触核蛋白病变，影响皮质下脑结构。基于冷冻电子显微镜，有报道称LBD的α-突触核蛋白细丝结构与MSA和青少年型突触核蛋白病（JOS）不同。罕见的非典型MSA亚型在边缘系统中显示出丰富的神经元嗜银性α-突触核蛋白包涵体。目前的观点表明，疾病实体以独特的原纤维折叠为特征。在这里，我们证明α-突触核蛋白可以形成路易体-多系统萎缩混合折叠，导致MSA的非典型组织病理学形式。蛋白酶敏感性消化试验、种子扩增试验（SAA）和构象稳定性试验（CSA）所显示的α-突触核蛋白不同的生化特性也与细胞病理学差异有关。我们扩展了目前基于结构的突触核蛋白病分类，并提出细胞特异性蛋白质病变可能与不同的细丝折叠有关。
