Abstract
Nedd4 family interacting protein 1 (Ndfip1) is an adaptor of Nedd4-family ubiquitin ligases. Experimental results showed that Ndfip1 had a potential neuroprotective effect in neurology diseases. However, the neuroprotective effect and the underlying mechanisms of Ndfip1 in Parkinson's disease (PD) have not yet been fully elucidated. Therefore, in this study, we explored the neuroprotective effect of Ndfip1 against mitochondrial complex I inhibitor rotenone in a human dopaminergic neuroblastoma SH-SY5Y cell line and further elucidated its possible underlying mechanisms. Our results showed that rotenone could induce the up-regulation of α-synuclein (α-syn) in both mRNA and protein levels. The expression of Ndfip1 decreased at 24 h after rotenone treatment. Further study showed that high expression of Ndfip1 could protect SH-SY5Y cells against rotenone-induced neurotoxicity and antagonize the rotenone-induced increase in α-syn protein levels. In addition, high expression of Ndfip1 inhibited rotenone-induced increase in the protein levels of caspase-3 and decrease in tyrosine hydroxylase (TH). Further study showed that Ndfip1 did not affect the protein expression of iron regulatory protein 1 (IRP1), transferrin receptor 1 (TfR1), while antagonized the increase in protein levels of P62 and ferritin L caused by rotenone. Our findings provide specific identification of Ndfip1 proteins to inhibit the increase of α-syn in rotenone-induced SH-SY5Y cells. Ndfip1 might be a new theoretical drug target for the prevention and treatment of PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disease caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra (SN)
Results showed that 300 nmol/L rotenone could significantly increase the mRNA expression of α-syn at 12 and 24 h compared with the control (Figure 1A)
To investigate whether rotenone treatment could affect the expression of Nedd4 family interacting protein 1 (Ndfip1), we detected the expression of Ndfip1 in mRNA and protein levels
Summary
Parkinson’s disease (PD) is a neurodegenerative disease caused by progressive degeneration of dopamine (DA) neurons in the substantia nigra (SN). It has been shown that proteasome and lysosome play crucial roles in the degradation of misfolded and damaged proteins (Betarbet et al, 2005; Gan-Or et al, 2015). Failure of these pathways in the brain was associated with neuropathological disorders including PD (Moore et al, 2005). Studies have shown that aggregation of α-syn in the SN of patients with PD was accompanied by an up-regulation of Ndfip (Howitt et al, 2014), but the relationship between them and the possible mechanisms of their actions in PD were not fully elucidated
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