Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158;
Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
Proc Natl Acad Sci U S A. 2022 Feb 8;119(6). doi: 10.1073/pnas.2113489119.
The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.
α-突触核蛋白可以采取几种不同的构象，从而导致神经退行性变。不同的α-突触核蛋白构象至少导致三种不同的α-突触核蛋白病：多系统萎缩症（MSA）、路易体痴呆症（DLB）和帕金森病（PD）。在早期研究中，我们将 MSA 传播到转基因（Tg）小鼠和表达突变型α-突触核蛋白（A53T）的培养 HEK 细胞中，但没有传播到表达α-突触核蛋白（E46K）的细胞中。现在，我们报告说，DLB 是由一种不同于 MSA 的α-突触核蛋白朊病毒引起的。使用表达突变型α-突触核蛋白（E46K）的培养 HEK 细胞，我们发现 DLB 朊病毒可以传播到这些 HEK 细胞。我们的结果表明，第三种α-突触核蛋白朊病毒可能导致 PD，但需要进一步的研究来鉴定表达允许 PD 朊病毒复制的突变型α-突触核蛋白的细胞和/或 Tg 小鼠。我们的发现表明，其他α-突触核蛋白突变体应该进一步深入了解α-突触核蛋白朊病毒复制、菌株形成和疾病发病机制，所有这些都可能有助于发现治疗 PD 以及其他α-突触核蛋白病的有效药物。
