Torre-Muruzabal Teresa, Van der Perren Anke, Coens Audrey, Gelders Géraldine, Janer Anna Barber, Camacho-Garcia Sara, Klingstedt Therése, Nilsson Peter, Stefanova Nadia, Melki Ronald, Baekelandt Veerle, Peelaerts Wouter
KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium.
Institut François Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France.
Brain. 2023 Jan 5;146(1):237-251. doi: 10.1093/brain/awac061.
Multiple system atrophy is a progressive neurodegenerative disease with prominent autonomic and motor features. During early stages, different subtypes of the disease are distinguished by their predominant parkinsonian or cerebellar symptoms, reflecting its heterogeneous nature. The pathognomonic feature of multiple system atrophy is the presence of α-synuclein (αSyn) protein deposits in oligodendroglial cells. αSyn can assemble in specific cellular or disease environments and form αSyn strains with unique structural features, but the ability of αSyn strains to propagate in oligodendrocytes remains elusive. Recently, it was shown that αSyn strains with related conformations exist in the brains of patients. Here, we investigated whether different αSyn strains can influence multiple system atrophy progression in a strain-dependent manner. To this aim, we injected two recombinant αSyn strains (fibrils and ribbons) in multiple system atrophy transgenic mice and found that they determined disease severity in multiple system atrophy via host-restricted and cell-specific pathology in vivo. αSyn strains significantly impact disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. Spectral analysis showed that ribbons propagated oligodendroglial inclusions that were structurally distinct from those of fibrils, with resemblance to oligodendroglial inclusions, in the brains of patients with multiple system atrophy. This study, therefore, shows that the multiple system atrophy phenotype is governed by both the nature of the αSyn strain and the host environment and that by injecting αSyn strains into an animal model of the disease, a more comprehensive phenotype can be established.
多系统萎缩是一种具有突出自主神经和运动特征的进行性神经退行性疾病。在疾病早期，不同亚型以其主要的帕金森样或小脑症状来区分，这反映了其异质性。多系统萎缩的特征性表现是少突胶质细胞中存在α-突触核蛋白（αSyn）蛋白沉积。αSyn可在特定细胞或疾病环境中组装并形成具有独特结构特征的αSyn毒株，但αSyn毒株在少突胶质细胞中传播的能力仍不清楚。最近的研究表明，具有相关构象的αSyn毒株存在于患者大脑中。在此，我们研究了不同的αSyn毒株是否能以毒株依赖的方式影响多系统萎缩的进展。为此，我们将两种重组αSyn毒株（纤维状和带状）注射到多系统萎缩转基因小鼠体内，发现它们通过体内宿主限制和细胞特异性病理决定了多系统萎缩的疾病严重程度。αSyn毒株通过少突胶质细胞、神经毒性和免疫相关机制以毒株依赖的方式显著影响疾病进展。神经退行性变和脑萎缩伴随着独特的小胶质细胞和星形胶质细胞反应以及中枢和外周免疫细胞的募集。小胶质细胞的差异激活在体外和体内均与αSyn毒株的结构特征相关。光谱分析表明，带状毒株在多系统萎缩患者大脑中传播的少突胶质细胞包涵体在结构上与纤维状毒株不同，与多系统萎缩患者大脑中的少突胶质细胞包涵体相似。因此，本研究表明，多系统萎缩表型受αSyn毒株的性质和宿主环境共同控制，并且通过将αSyn毒株注射到该疾病的动物模型中，可以建立更全面的表型。
