Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons and the aggregation of Lewy bodies in the substantia nigra pars compacta (SNpc) [1]. Motor problems (including bradykinesia, rigidity, and tremor), along with non-motor issues (like sleep disturbance, sensory dysfunction, and constipation) manifest when DA neuron loss reaches approximately 50% [2,3]. Despite available dopamine replacement therapies alleviating motor symptoms, none effectively prevent DA neuron degeneration [4]. Therefore, there is an urgent need to explore novel therapies to halt DA neuron loss.

Current research indicates that oxidative stress, inflammation, autophagy and ferroptosis contribute to PD initiation and progression [[5], [6], [7]]. Ferroptosis, in particular, plays a crucial role in PD pathogenesis [8]. This form of cell death arises from abnormal iron metabolism, lipid peroxidation and ROS accumulation [9]. Studies found that elevated nigral iron and metabolic disorders are observed in PD patients, accompanied by increased ROS and lipid peroxidation in the SNpc [[10], [11], [12]]. Notably, the ferroptosis inhibitor ferrostatin-1 prevents cell death in PD models, and iron chelation therapy shows promise in ameliorating motor symptoms [[13], [14], [15], [16]]. Inhibition of ferroptosis emerges as a potential strategy for PD treatment [17], although the molecular mechanism remains unclear.

Dysfunctional mitochondria are major sources of mitochondrial reactive oxygen species (mtROS) [18]. Mitophagy, the process of eliminating dysfunctional mitochondria and mtROS, is crucial [19]. Studies indicate that ferroptosis is dependent on mtROS generation, and the mitochondria-targeted antioxidant mito-TEMPO effectively inhibits ferroptosis [20,21]. This highlights the need to investigate the interplay between mitophagy and ferroptosis as a potential therapeutic target for various diseases. However, this interaction has not been studied in the context of PD.

As a well-explored ion transporter, Na+/K+-ATPase (NKA) is ubiquitously expressed in most mammalian cells [22]. It plays essential roles in regulating various cellular processes, including maintenance of membrane potential and modulation of signal transduction pathways [22,23]. Recent reports have highlighted the involvement of NKA dysfunction in exacerbating neurodegeneration across various neurodegenerative diseases [24,25]. Intriguingly, both pharmacological and genetic suppression of NKA have been strongly linked to Parkinson's disease (PD) and rapid-onset dystonia-parkinsonism (RDP) [[26], [27], [28]]. For instance, reduced NKA activity has been observed in the erythrocytes of PD patients and PD rodent models [[29], [30], [31], [32]]. Moreover, our laboratory discovered that NKAα1 forms a complex with α-synuclein (α-syn) and AMPKα upon stimulation with PFF (a type of α-synuclein assembly) [33]. This NKAα1/α-syn/AMPKα complex serves to mitigate AMPKα-dependent autophagy, thereby promoting exacerbation of DA neuron loss [33]. Other research teams have also identified that NKAα3 forms a complex with α-syn, influencing intracellular calcium homeostasis and aggravating DA neuron loss [34]. However, the precise role of NKAα1 in MPTP-induced PD remains unclear. Notably, a specific antibody (DR-Ab) targeting the DR-region (897DVEDSYGQQWTYEQR911) of the NKAα subunit has been identified to activate NKAα1 [35,36]. Additionally, both our group and others have demonstrated that DR-Ab treatment enhances the activity and membrane expression level of NKAα1, addressing damaged mitochondria [37] and alleviating autophagy deficiency [38]. Given the pivotal role of NKAα1 in PD, our inquiry focuses on whether DR-Ab can impede the progression of MPTP-induced PD.

In this study, we aim to elucidate the crucial role of NKAα1 in the MPTP model, utilizing NKAα1+/− mice. Furthermore, we seek to delineate the neuroprotective effects of DR-Ab both in vivo and in vitro. The inhibition of mitophagy-dependent ferroptosis identified in this study may offer a promising therapeutic target for PD. Overall, these findings contribute to the accelerated discovery of novel therapeutic strategies against PD associated with NKAα1 deficiency.