Silencing RNF13 Alleviates Parkinson's Disease - Like Problems in Mouse Models by Regulating the Endoplasmic Reticulum Stress-Mediated IRE1α-TRAF2-ASK1-JNK Pathway.

The objective of this study was to understand if RNF13 can affect Parkinson's disease (PD) model mice by modulating the endoplasmic reticulum stress (ERS)-mediated IRE1α-TRAF2-ASK1-JNK pathway. C57BL/6 mice injected with MPTP to establish PD mice models were divided into Control, MPTP, MPTP + sh-RNF13, and MPTP + sh-NC groups. Rotarod, balance beam, and open-field tests were used to assess the behavioral changes of experimental mice. Immunofluorescence assay was used to determine TH-positive expression in substantia nigra, TUNEL staining to detect apoptosis, and Western blotting to measure the expression of IRE1α-TRAF2-ASK1-JNK pathway. Besides, SH-SY5Y cells treated with MPP+ were assigned into Control, MPP+, MPP+ + sh-RNF13, and MPP+ + sh-NC groups in vitro to detect cell viability, apoptosis and Ca2+ level. When compared with those Control mice, MPTP mice showed decreased retention time spent on rotarod performance and prolonged time on balance beam test, as well as evident reductions in floor plane (FP) movements, moving time, moving distance, and mean velocity in open-field test, which had an obvious increase of TUNEL-positive cells, significant decrease of TH-positive cells, and remarkable up-regulations of RNF13, p-IRE1α/IRE1α, TRAF2, ASK1, and p-JNK/JNK. Meanwhile, MPTP mice treated with sh-RNF13 were improved in all above indexes. In vitro, MPP+ treated SH-SY5Y cells had decreased cell viability and increased cell apoptosis, as well as the upregulated IRE1α-TRAF2-ASK1-JNK pathway proteins and Ca2+ level. RNF13 knockdown improved all above indexes in SH-SY5Y cells treated with MPP+. Silencing RNF13 can alleviate motor dysfunction and dopamine neuronal damage in PD mice by inhibiting ERS-mediated IRE1α-TRAF2-ASK1-JNK pathway.