Search

Apoptosis has been implicated as one of the important mechanisms involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). Increasing evidence suggests that Ndfip1 is a neuroprotective protein, and Ndfip1-mediated protein ubiquitination might be a possible survival strategy in neuronal injury. The aim of the present study is to investigate the neuroprotective effect of Ndfip1 on 1-methyl-4-phenylpyridinium (MPP + )-treated MES23.5 cells and the underlying mechanisms. Results showed that overexpression of Ndfip1 could significantly attenuate MPP + -induced cell loss and nuclear condensation. Further experiments demonstrated that Ndfip1 could increase Bcl-2/Bax ratio, suppress cytochrome c release from the mitochondria to cytoplasm and decrease caspase-3 activation induced by MPP + . These results suggested that Ndfip1 protected MES23.5 cells against MPP + by its anti-apoptotic effect. In addition, we found that Ndfip1 overexpression could decrease the protein level of dopamine transporter (DAT). In parallel, proteasome inhibitor MG132 could markedly reverse Ndfip1-induced degradation of DAT. These data suggest that Ndfip1 exerts its inhibitory effect on DAT by modulating DAT degradation, in which ubiquitin–proteasome system activation might be involved. Collectively, our study indicated that the ability to decrease the DAT of Ndfip1 might be one of the mechanisms underlying its protective effect on MPP + -induced cell damage in MES23.5 cells. [ABSTRACT FROM AUTHOR]

Abstract: Ghrelin, a 28-amino acid peptide, is an endogenous ligand for the growth hormone secretagogue (GHS) receptor. Our previous data showed that ghrelin could inhibit apoptosis in Parkinson''s disease (PD) models both in vitro and in vivo. There is now growing evidence that oxidative stress has a critical role in the etiology of PD. And ghrelin was reported to possess anti-inflammatory, antioxidant effects. Dose ghrelin protect dopaminergic neurons by its antioxidant effect? In the present study, 1-methyl-4-phenylpyridinium (MPP+) was used to evaluate the possible antioxidant effects of ghrelin on MPP+-induced neurotoxicity in MES23.5 cells and the underlying mechanisms. Our results showed that MPP+ significantly increased malonaldehyde (MDA) level and Bax/Bcl2 ratio, reduced the level of Cu–Zn superoxide dismutase (SOD) and catalase (CAT). Ghrelin protected MES23.5 cells against MPP+-induced neurotoxicity by reversing these changes. Furthermore, ghrelin pretreatment significantly inhibited MPP+-induced nuclear factor-kappaB translocation. These results suggest that the protective effects of ghrelin on MPP+-induced cytotoxicity may be ascribed to its antioxidative properties, and the modulation of nuclear factor-kappaB. [Copyright &y& Elsevier]

Increasing evidence has shown that mitochondrial dysfunction and iron accumulation contribute to the pathogenesis of Parkinson's disease (PD). Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein of the Nedd4 E3 ubiquitin ligases. We have previously reported that Ndfip1 showed a neuroprotective effect in cell models of PD. However, whether Ndfip1 could protect dopaminergic neurons in PD animal models in vivo and the possible mechanisms are not known. Here, our results showed that the expression of Ndfip1 decreased in the substantia nigra (SN) of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model. Overexpression of Ndfip1 could improve MPTP-induced motor dysfunction significantly and antagonize the loss of dopaminergic neurons in the SN of MPTP-induced mice. Further study showed that overexpression of Ndfip1 might protect against MPTP-induced neurotoxicity through regulation of voltage-dependent anion-selective channel (VDAC). In addition, we observed the downregulation of Ndfip1 and upregulation of VDAC1/2 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced SH-SY5Y cells. Furthermore, high expression of Ndfip1 in SH-SY5Y cells inhibited MPP+-induced increase of VDAC1/2 and restored MPP+-induced mitochondrial dysfunction. Furthermore, Ndfip1 prevented MPP+-induced increase in the expression of long-chain acyl-CoA synthetase 4 (ACSL4), suggesting the possible role of Ndfip1 in regulating ferroptosis. Our results provide new evidence for the neuroprotective effect of Ndfip1 on dopaminergic neurons in PD animal models and provide promising targets for the treatment of iron-related diseases, including PD. • Ndfip1 protected against MPTP-induced motor deficits and loss of dopaminergic neurons. • Ndfip1 inhibited MPP+-induced increase of VDAC1/2 and mitochondrial dysfunction. • Ndfip1 prevented MPP+-induced ferroptosis by downregulation of ACSL4. [ABSTRACT FROM AUTHOR]

Abnormal iron accumulation has been implicated in the etiology of Parkinson's disease (PD). Understanding how iron damages dopaminergic neurons in the substantia nigra (SN) of PD is particularly important for developing targeted neurotherapeutic strategies for the disease. However, it is still not fully understood how excess iron contributes to the neurodegeneration of dopaminergic neurons in PD. There has been increased attention on mitochondrial iron dyshomeostasis, iron-induced mitochondrial dysfunction and ferroptosis in PD. Therefore, this review begins with a brief introduction to describe cellular iron metabolism and the dysregulation of iron metabolism in PD. Then we provide an update on how iron is delivered to mitochondria and induces the damage of dopaminergic neurons in PD. In addition, we also summarize new research progress on iron-dependent ferroptosis in PD and mitochondria-localized proteins involved in ferroptosis. This will provide new insight into potential therapeutic strategies targeting mitochondrial iron dysfunction. • Dysregulation of iron transporters contributes to iron accumulation in PD. • Mitochondrial iron dyshomeostasis is involved in mitochondrial dysfunction and ferroptosis. • Targeting mitochondrial iron dyshomeostasis is a therapeutic target for PD. [ABSTRACT FROM AUTHOR]