Acrylamide Induces Protein Aggregation in CNS through Suppression of FoxO1-mediated Autophagy

Abstract

ABSTRACTProteotoxic stress is a major stimulus and risk factor for the neuropathogenesis in central nervous system (CNS), which is tightly associated with neurodegenerative diseases. Here, we identify acrylamide (ACR), a type-2 alkene that is commonly detected in deep-fried starch food and used in water industry and biomedical laboratories, as a potent and universal inducer of proteotoxic stress in mouse brain, as well as in cultured mouse neural stem cells, neurons and astrocytes, three major cell types in CNS. Aggregations of ubiquitin-labeled misfolded proteins and neurodegeneration-related proteins including amyloid precursor protein and presenilin 1 were drastically induced by ACR, leading to cell-defensive aggresome formation that was able to temporarily counteract with ACR toxicity. However, a defected clearance of aggresomes eventually led to apoptotic cell death, which was largely attributed to the breakdown of cytoskeleton and impairment of macroautophagy/autophagy, as evidenced by an aggregation of filament actin and an almost complete loss of LC3-positive autophagosomes. A series of core autophagy-related genes responsible for autophagosome formation were down-regulated, indicating an ACR-induced transcriptional suppression of autophagy. In addition, FoxO1, the master transactivator of these genes, were both transcriptionally repressed and nuclear excluded by ACR. Overexpression of FoxO1 rescued ACR-induced autophagy defects and attenuated the proteotoxicity. In summary, we spotlight proteotoxic stress as a novel feature of ACR neurotoxicity in CNS, and implicate FoxO1 as a critical therapeutic target.