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

Abstract

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.

Toxicogenomics of iron oxide nanoparticles in the nematodeC. elegans

“…(Li et al, 2012a, Wu et al, 2015, Scharf et al, 2016 SPION exposure also modulated the expression of clathrin and dynamin, suggesting that SPIONs are taken up via endocytosis, which aligns well with previously reported results. (Tsyusko et al, 2012, Li et al, 2015 SPIONs also exerted significant effects on the expression of genes involved in the structure and integrity of the intestinal barrier (act-5, eps-8 and elt-2).…”

“…In particular, Scharf et al found that protein homeostasis was a major target of SiO 2 -NPs. (Scharf et al, 2016) The similar effect of both SPIONs on the lysosomal compartment suggests that this 'dustbin' organelle might be part of the cellular NP detoxifying mechanism, consistent with previous reports that endosome formation is an instrumental component of NP toxicity in vivo. (Tsyusko et al, 2012, Maurer et al, 2016, Zhang et al, 2016 …”

Aging by pollutants: introducing the aging dose (AD)50

“…Life span-resolved toxicology in adult hermaphrodite C. elegans involves cultivation in 96-well microtiter plates, where each well represents the microenvironment that holds all imaginable options for variation. In the presence of pollutants characteristic aging stigmata can be analyzed in differently aged adult nematodes such as (i) decrease in the rate of locomotion, swimming and pharyngeal pumping, (ii) disorganization of organ morphology (e.g., pharynx, intestine, body wall muscles), (iii) impaired protein homeostasis and increased amyloid formation or (iv) increased neurodegeneration [3,14,15,18]. A representative target of aging is the decline of neuromuscular fitness which can be quantified by plotting the number of worms that show a certain agerelated phenotype against the age of the worms in days ( Fig.…”

“…c Representative for certain other pollutants nano-silica accelerates organismal aging that manifests in biochemical, morphological and neurobehavioral phenotypes. Life span-resolved analyses reveal that hallmarks of aging (black arrows) occur prematurely (light gray arrows), as early as on day 2, in wild-type C. elegans exposed to silica nanoparticles [10,14,15] (Additional file 1: Table S1) promotes neurodegeneration of the HSN, disturbs serotonergic signaling in HSN which in turn leads to malfunction of the vulval neuromuscular circuit, a defective vulva and internal hatch [11,15] (Fig. 2).…”

“…Schematic depicting a cascade of neurotoxic events that underlie the impairment of reproduction by nanomaterials in the adult hermaphrodite nematode C. elegans. HSN, hermaphrodite specific neuron [11,15] Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.…”