Blumenstock Sonja, Rodrigues Eva F, Peters Finn, Blazquez-Llorca Lidia, Schmidt Felix, Giese Armin, Herms Jochen
Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
EMBO Mol Med. 2017 May;9(5):716-731. doi: 10.15252/emmm.201607305.
Although misfolded and aggregated α-synuclein (α-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how α-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term imaging of apical dendrites was performed in mice overexpressing wild-type human α-synuclein. Additionally, intracranial injection of preformed α-synuclein fibrils was performed to induce cortical α-syn pathology. We find that α-synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age-dependent manner. We also provide evidence for the detrimental effects of seeded α-synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology .
尽管错误折叠和聚集的α-突触核蛋白（α-syn）在突触核蛋白病的疾病进展中已被确认，但其在皮质回路损伤和突触可塑性方面的作用仍未完全明确。我们采用两种不同方法研究了α-突触核蛋白积累如何影响小鼠体感皮层的突触可塑性。对过表达野生型人α-突触核蛋白的小鼠进行顶树突的长期成像。此外，进行颅内注射预形成的α-突触核蛋白纤维以诱导皮质α-突触核蛋白病变。我们发现，过表达α-突触核蛋白的小鼠以年龄依赖性方式表现出棘密度降低和棘动态异常。我们还提供了证据表明种子化的α-突触核蛋白聚集体对树突结构有有害影响。我们观察到V层锥体神经元出现棘丢失以及树突干营养不良性变形。我们的结果为与突触核蛋白病相关的痴呆症潜在病理生理学提供了联系，并可能有助于评估针对树突棘病理的潜在候选药物。
