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- Title
IGFBP5 Promotes Neuronal Apoptosis in a 6-OHDA-Toxicant Model of Parkinson's Disease by Inhibiting the Sonic Hedgehog Signaling Pathway.
- Authors
Guo, Shenglong; Lei, Qi; Yang, Qian; Chen, Ruili
- Abstract
Introduction: Parkinson's disease (PD) is the most common neurodegenerative disease worldwide. Studies have shown that insulin-like growth factor-binding protein 5 (IGFBP5) may contribute to methamphetamine-induced neurotoxicity and neuronal apoptosis in PC-12 cells and rat striatum. Here, we studied the expression and role of IGFBP5 in the 6-OHDA-toxicant model of PD. Methods: PC-12 and SH-SY5Y cells were exposed to 50 μm 6-OHDA for 24 h. qRT-PCR, western blotting, CCK-8 assay, EdU staining, annexin V staining, and immunofluorescence were performed to study the effects of IGFBP5-specific siRNAs. The effects of IGFBP5 on a rat 6-OHDA model of PD were confirmed by performing behavioral tests, tyrosine hydroxylase (TH) immunofluorescence staining, and western blotting. Results: In the GSE7621 dataset, IGFBP5 was highly expressed in the substantia nigra tissues of PD patients compared to healthy controls. In PC-12 and SH-SY5Y cells, IGFBP5 was upregulated following 6-OHDA exposure in a dose-dependent manner. Silencing of IGFBP5 promoted PC-12 and SH-SY5Y proliferation and inhibited apoptosis under 6-OHDA stimulation. Silencing of IGFBP5 relieved 6-OHDA-induced TH-positive neuron loss. Hedgehog signaling pathway was predicted as a downstream signaling pathway of IGFBP5. Negative regulation between IGFBP5 and sonic hedgehog (SHH) signaling pathway was confirmed in vitro. The effects of IGFBP5 silencing on SH-SY5Y cells were partially reversed using cyclopamine, a direct inhibitor of the SHH signaling pathway. In addition, silencing of IGFBP5 attenuated motor deficits and neuronal damage in 6-OHDA-induced PD rats. Conclusion: Elevated IGFBP5 expression may be involved in 6-OHDA-induced neurotoxicity through regulation of the SHH signaling pathway. Highlights of the Study: IGFBP5 was highly expressed in a 6-OHDA-toxicant model of PD. Silencing of IGFBP5 promotes proliferation of 6-OHDA-treated neurons, alleviates apoptosis of 6-OHDA-treated neurons, and inhibits the loss of TH-positive neurons. Silencing of IGFBP5 is neuroprotective due to regulation of sonic hedgehog signaling pathway.
- Subjects
PARKINSON'S disease; CELLULAR signal transduction; INSULIN-like growth factor-binding proteins; APOPTOSIS; LABORATORY rats; METHAMPHETAMINE; CARBIDOPA
- Publication
Medical Principles & Practice, 2024, Vol 33, Issue 3, p269
- ISSN
1011-7571
- Publication type
Article
- DOI
10.1159/000538467