Perni Michele, van der Goot Annemieke, Limbocker Ryan, van Ham Tjakko J, Aprile Francesco A, Xu Catherine K, Flagmeier Patrick, Thijssen Karen, Sormanni Pietro, Fusco Giuliana, Chen Serene W, Challa Pavan K, Kirkegaard Julius B, Laine Romain F, Ma Kai Yu, Müller Martin B D, Sinnige Tessa, Kumita Janet R, Cohen Samuel I A, Seinstra Renée, Kaminski Schierle Gabriele S, Kaminski Clemens F, Barbut Denise, De Simone Alfonso, Knowles Tuomas P J, Zasloff Michael, Nollen Ellen A A, Vendruscolo Michele, Dobson Christopher M
Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge, United Kingdom.
University Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen, Netherlands.
Front Cell Dev Biol. 2021 Mar 22;9:552549. doi: 10.3389/fcell.2021.552549. eCollection 2021.
The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two models of PD (PD and PD), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PD). PD worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PD worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PD worms compared to PD and PD worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PD and PD worms, but had less marked effects in PD. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PD, PD and PD worms. These results illustrate the use of these two models in fundamental and applied PD research.
α-突触核蛋白的聚集是帕金森病（PD）以及多种相关神经疾病的一个标志。该蛋白的一些突变，包括A30P和A53T，与家族性形式的疾病相关。携带A30P突变的患者通常表现出与散发性PD相似的发病年龄和症状，而携带A53T突变的患者一般发病年龄更早且病情进展加速。我们报告了两种PD模型（PD和PD），它们在肌肉细胞中表达这些突变变体，并探究了它们相对于表达野生型蛋白的动物（PD）的行为。PD线虫的运动速度降低，麻痹率增加，与对照线虫相比，身体弯曲频率没有变化。相比之下，在PD线虫中，身体弯曲的速度和频率均显著降低，麻痹率增加。与PD和PD线虫相比，还观察到α-突触核蛋白在PD线虫中较少聚集形成聚集体，尽管α-突触核蛋白的表达水平相当，但在动物生命后期淀粉样特征明显。此外，鲨胺是一种目前正在进行治疗PD症状方面临床试验的天然产物，发现它能显著减少α-突触核蛋白在PD和PD线虫中的聚集及其相关毒性，但在PD中的作用不太明显。此外，使用一种靶向α-突触核蛋白N端区域的抗体，我们观察到在PD、PD和PD线虫中毒性受到抑制。这些结果说明了这两种模型在PD基础研究和应用研究中的用途。
