Anti-amyloid compounds protect from silica nanoparticle-induced neurotoxicity in the nematode C. elegans

Identifying nanomaterial-bio-interactions are imperative due to the broad introduction of nanoparticle (NP) applications and their distribution. Here, we demonstrate that silica NPs effect widespread protein aggregation in the soil nematode Caenorhabditis elegans ranging from induction of amyloid in nucleoli of intestinal cells to facilitation of protein aggregation in body wall muscles and axons of neural cells. Proteomic screening revealed that exposure of adult C. elegans with silica NPs promotes segregation of proteins belonging to the gene ontology (GO) group of “protein folding, proteolysis and stress response” to an SDS-resistant aggregome network. Candidate proteins in this group include chaperones, heat shock proteins and subunits of the 26S proteasome which are all decisively involved in protein homeostasis. The pathway of protein homeostasis was validated as a major target of silica NPs by behavioral phenotyping, as inhibitors of amyloid formation rescued NP-induced defects of locomotory patterns and egg laying. The analysis of a reporter worm for serotonergic neural cells revealed that silica NP-induced protein aggregation likewise occurs in axons of HSN neurons, where presynaptic accumulation of serotonin, e.g. disturbed axonal transport reduces the capacity for neurotransmission and egg laying. The results suggest that in C. elegans silica NPs promote a cascade of events including disturbance of protein homeostasis, widespread protein aggregation and inhibition of serotonergic neurotransmission which can be interrupted by compounds preventing amyloid fibrillation.

鉴于纳米颗粒（nanoparticle, NP）应用的广泛推广与分布，解析纳米材料-生物相互作用已成为亟需开展的研究课题。本研究证实，二氧化硅纳米颗粒可在模式生物秀丽隐杆线虫（Caenorhabditis elegans）中引发广泛的蛋白质聚集：从肠细胞核仁内淀粉样蛋白的诱导生成，到体壁肌肉与神经细胞轴突内蛋白质聚集的促进。蛋白质组筛选结果显示，成年秀丽隐杆线虫暴露于二氧化硅纳米颗粒后，可促使隶属于基因本体（Gene Ontology, GO）"蛋白质折叠、蛋白水解与应激反应"类别的蛋白质，向抗十二烷基硫酸钠（SDS）的聚集组网络发生富集。该类别中的候选蛋白包括分子伴侣、热休克蛋白以及26S蛋白酶体亚基，上述蛋白均与蛋白质稳态调控密切相关。通过行为表型分析可证实，蛋白质稳态通路是二氧化硅纳米颗粒的主要作用靶点：淀粉样蛋白形成抑制剂可逆转纳米颗粒诱导的运动模式缺陷与产卵异常。针对5-羟色胺能神经细胞的报告基因线虫分析显示，二氧化硅纳米颗粒诱导的蛋白质聚集同样会出现在HSN神经元的轴突中：此处5-羟色胺的突触前积累（如轴突运输紊乱）会降低神经传递与产卵能力。本研究结果表明，在秀丽隐杆线虫体内，二氧化硅纳米颗粒可触发一系列级联事件：包括蛋白质稳态紊乱、广泛的蛋白质聚集以及5-羟色胺能神经传递抑制，而上述过程可被阻断淀粉样蛋白纤维化的化合物所终止。