Hallbeck Martin, Ekmark-Lewén Sara, Kahle Philipp J, Ingelsson Martin, Reyes Juan F
Department of Biomedical and Clinical Sciences, Department of Clinical Pathology, Linköping University, Linköping, Sweden.
Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
iScience. 2024 Nov 23;27(12):111448. doi: 10.1016/j.isci.2024.111448. eCollection 2024 Dec 20.
Accumulating evidence demonstrates that alpha-synuclein (α-syn) pathology associated with Parkinson's disease (PD) is not limited to the brain, as it also appears in a select number of peripheral tissues including the liver. In this study, we identified a number of PD-associated α-syn post-translational modifications in the livers of (Thy-1)-h[A30P] mice, a mouse model of familial PD expressing human α-syn harboring the A30P mutation driven by a neuron-specific promoter. , we also demonstrate that human hepatocytes induce post-translational modifications following α-syn fibrillar (PFF) treatment. Moreover, such cells also degrade PFFs over time, whereas oligomeric assemblies are more resistant to degradation, but this process can be enhanced by autophagy stimulators. Collectively, our findings suggest that pathological α-syn is transported to the liver in a modified state or is modified upon arrival, which facilitates its clearance and detoxification, pointing to a role for the liver in the degradation of PD-associated pathology.
越来越多的证据表明，与帕金森病（PD）相关的α-突触核蛋白（α-syn）病变并不局限于大脑，因为它也出现在包括肝脏在内的一些外周组织中。在本研究中，我们在（Thy-1）-h[A30P]小鼠的肝脏中鉴定出了一些与PD相关的α-syn翻译后修饰，（Thy-1）-h[A30P]小鼠是一种家族性PD小鼠模型，表达由神经元特异性启动子驱动的携带A30P突变的人α-syn。我们还证明，人肝细胞在α-syn纤维原纤维（PFF）处理后会诱导翻译后修饰。此外，随着时间的推移，这些细胞也会降解PFF，而寡聚体组装对降解更具抗性，但自噬刺激剂可以增强这一过程。总的来说，我们的研究结果表明，病理性α-syn以修饰状态转运到肝脏或在到达后被修饰，这有助于其清除和解毒，表明肝脏在PD相关病变的降解中发挥作用。
