α-Synuclein strains target distinct brain regions and cell types
α-Synuclein strains target distinct brain regions and cell types
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DOI：
10.1038/s41593-019-0541-x
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发表时间：
2020-01-01
影响因子：
25
通讯作者：
Watts, Joel C.
中科院分区：
文献类型：
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作者：
Lau, Angus;So, Raphaella W. L.;Watts, Joel C.
Lau等人发现α -突触核蛋白毒株注射到小鼠体内后会引发不同的疾病，这为帕金森病与相关神经退行性疾病的临床和病理差异提供了潜在的分子解释。突触核蛋白病（如帕金森病）和多系统萎缩之间的临床和病理差异被认为源于α -突触核蛋白聚集体的独特菌株，类似于朊病毒疾病中发生的情况。在这里，我们证明了用不同菌株的重组或脑源性α -突触核蛋白聚集体接种转基因小鼠会产生临床和病理上不同的疾病。在神经系统疾病的症状、发病时间、大脑α -突触核蛋白沉积物的形态和诱导聚集体的构象性质等方面观察到菌株特异性差异。此外，不同的菌株靶向大脑内不同的细胞群和细胞类型，概括了在人类突触核蛋白病中观察到的选择性靶向。连续传代后，菌株特异性的临床、病理和生化差异得以保持，这表明α -突触核蛋白是通过朊病毒样构象模板传播的。因此，致病性α -突触核蛋白表现出朊病毒菌株的关键特征，这证明了突触核蛋白病之间的疾病异质性是由不同的α -突触核蛋白菌株引起的。
Lau et al. find that alpha-synuclein strains initiate distinct diseases when injected into mice, which provides a potential molecular explanation for the clinical and pathological differences between Parkinson's disease and related neurodegenerative disorders.The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of alpha-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived alpha-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral alpha-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.