RESUMO
Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1+/-) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/- mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.
Assuntos
Neurônios Dopaminérgicos , Ferroptose , Mitofagia , Doença de Parkinson , ATPase Trocadora de Sódio-Potássio , Animais , Mitofagia/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Camundongos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/genética , Doença de Parkinson/tratamento farmacológico , Humanos , Masculino , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Haploinsuficiência , Camundongos KnockoutRESUMO
Semaphorin 3B (SEMA-3B), which belongs to the semaphorin family, has an important role in cell apoptosis and inhibition of angiogenesis. A previous study by our group revealed that SEMA-3B was downregulated in tumor tissues of patients with hepatocellular carcinoma (HCC) and exerts anti-motility and anti-invasion effects on tumor cells. However, the serum levels of SEMA-3B and their clinical significance have remained elusive; therefore, the aim of the present study was to monitor its expression in HCC and investigate its clinical significance. ELISA was used to determine the serum levels of SEMA-3B in 132 patients with HCC and 57 healthy individuals. The association between SEMA-3B and clinicopathological parameters was investigated. Serum SEMA-3B was indicated to be significantly decreased in patients with HCC as compared with that in the controls (P<0.05) and it was negatively associated with tumor size (P=0.039), encapsulation (P=0.002) and TNM stage (P=0.034). The prognosis of patients with low expression of SEMA-3B was poor. In conclusion, the results of the present study revealed that serum SEMA-3B is decreased in HCC and is negatively associated with prognosis; therefore, it may be used as a prognostic marker in HCC.