MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
Acta Neuropathol Commun. 2021 Nov 24;9(1):189. doi: 10.1186/s40478-021-01291-7.
Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.
外周给予（口服、鼻内、腹腔内、静脉内）组装的 A53T α-突触核蛋白会在携带人突变 A53T α-突触核蛋白（M83 系）的杂合子转基因小鼠中诱导突触核蛋白病。当通过腹腔内、静脉内或肌肉内给予具有 II 型 α-突触核蛋白丝的多系统萎缩病例的小脑提取物时，也是如此。我们观察到大量的 pS129 α-突触核蛋白在神经细胞中具有免疫反应性，并且严重的运动障碍导致后肢瘫痪和寿命缩短。可检测到 pS129 α-突触核蛋白免疫反应性的纤维。在腹腔内注射组装的 A53T α-突触核蛋白或具有 II 型 α-突触核蛋白丝的小脑提取物五个月后，会出现 70%的运动神经元丧失，这来自于一个经病理证实的多系统萎缩病例。小胶质细胞从主要的分支状变为营养不良的外观。综上所述，这些发现表明神经细胞中 α-突触核蛋白包涵体的形成与神经退行性变密切相关，伴随着小胶质细胞形态的改变。α-突触核蛋白包涵体的传播取决于种子和转基因表达蛋白的特性。
