Silica nanoparticles induce alpha-synuclein induction and aggregation in PC12-cells.
Silica nanoparticles (SiO2-NPs) are widely applied in diagnosis, imaging, and drug delivery of central nervous diseases. Previously, we found that SiO2-NPs enter the brain and, more specifically, the dopaminergic neurons in the striatum. Whether SiO2-NPs have neurotoxicity and contribute to development of Parkinson's disease (PD) remains unclear. In this study, we investigated the effect of SiO2-NPs on PC12 cells, a dopaminergic neuron-like cell line. We showed that SiO2-NPs up-regulated α-synuclein expression, and N-acetyl cysteine reduced α-synuclein. SiO2-NPs inhibited 20S proteasome activity and decreased ubiquitin, Parkin, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) protein levels in the ubiquitin-proteasome system (UPS). SiO2-NPs induced autophagy as shown by transmission electron microscopy, and elevated LC3-II and Beclin 1 levels in PC12 cells. SiO2-NPs inhibited phosphorylation of PI3K, Akt, mTOR, and P70S6. These data suggest that SiO2-NPs induce oxidative stress and α-synuclein aggregation by inhibiting the UPS. SiO2-NPs also induce autophagy through inhibiting PI3K-Akt-mTOR signaling, which is known to negatively regulate autophagy. Amyloid aggregates of α-synuclein in dopaminergic neurons of the midbrain are considered the hallmark of PD. Our findings indicate that SiO2-NPs exposure induces neurotoxicity and may be a significant risk factor for the development of PD.
Stomatology Department of Linyi People's Hospital, Linyi, Shandong, 276000, China.
Hongjun
H
Xie
Stomatology Department of Shandong Medical College, Linyi, Shandong, 276000, China. Electronic address: wujie19821126@sina.com.
Jie
J
Wu
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
D015415:Biomarkers; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D066329:Protein Aggregates; D051057:Proto-Oncogene Proteins c-akt; D012822:Silicon Dioxide; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin; D051844:alpha-Synuclein
Alpha-synuclein; Autophagy; Parkinson diseases; Silica nanoparticles; Ubiquitin-proteasome system