As a age-related neurodegenerative disorder, Parkinson's disease (PD) is clinically manifested by tremor, bradykinesia, gait dysfunction and postural instability (Jankovic, 2008). Approximately 1%–2% of the elderly people over 60 years of age are diagnosed with PD (de Lau et al., 2006). Age, oophorectomy, and inheritance are risk factors for sporadic PD. Age is the most critical cause among these factors documented so far (Bronstein et al., 2009). Aging population would cause surges in disease prevalence in the next decades, which would induce serious issues regarding health care and social security at a worldwide level (Dorsey et al., 2007). The degeneration of dopaminergic neurons in the substantia nigra pars compacta has been regarded as the hallmark of PD initiation (Dickson, 2012). Protein misfolding and aggregation, oxidative damage, neuroinflammation and mitochondrial dysfunction are possible culprits in PD pathogenesis (Schapira, 2011). Currently, various preventative strategies, including physical therapy, anti-inflammatory drugs and antioxidants, can ameliorate PD-related symptoms to some extent (Dong et al., 2020). However, currently available therapies for PD treatment cannot decelerate or stop the progression of PD. Therefore, there is an urgent need to understand the pathogenic mechanism at the molecular level and identify potential targets to develop novel therapeutic strategies for this disease.

As sequence-specific DNA-binding proteins, transcription factors serve as regulators of RNA synthesis based on a DNA template (Wang et al., 2017). In pathological processes of PD, the critical functions of transcription factors have been described previously. For example, the myocyte enhancer factor 2D (MEF2D) is a neuronal survival factor in PD (Yang et al., 2009). Additionally, nuclear receptor related 1 (Nurr1) reduces the secretion of proinflammatory cytokines in PD models (Liu et al., 2017). Moreover, paired like homeodomain 3 (Pitex3) upregulation promotes the production of neurotrophic factors and alleviates rotenone-induced injury for dopaminergic neurons (Tang et al., 2017). Signal transducers and activators of transcription (STATs) are critical transcription factors for the activation of many cytokines (Darnell et al., 1994; Iida et al., 2011). There are seven members of the mammalian STAT, including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 (Horvath, 2000). Inhibition of STAT1 pathway suppresses the inflammatory response in brain microglia and astrocytes (Kim et al., 2013). The regulation of STAT2 is a critical player in neuronal survival and excitability, improving cognitive impairments following sporadic PD dementia (Magalhaes et al., 2021). STAT3 is a transcription factor that regulates inflammation in microglia (Zhang et al., 2019). In a lipopolysaccharide-induced PD cell model, STAT3 knockdown inhibits inflammatory reaction and cell death (Wang et al., 2021). As reported, patients with PD have lower level of STAT4 compared with healthy subjects (De Francesco et al., 2021). However, the biological functions of STAT4 and its underlying mechanisms in PD pathogenesis are still uncertain.

Mitogen-activated protein kinases (MAPKs) are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis, survival, inflammation and innate immunity. In mammals, MAPKs include c-Jun NH2-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK) (Arthur et al., 2013; Peti et al., 2013). MAPK pathways are reported to be involved in the pathophysiology of PD (Jha et al., 2015; Shah et al., 2017). N-methyl-4-phenylpyridinium (MPP+), a naturally transformed from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), readily crosses the blood-brain barrier and is selectively imported in dopaminergic neurons, leading to PD-like motor symptoms (Martinez et al., 2012). MPP+ and MPTP have been previously used to establish in vitro and in vivo models of PD (Gubellini et al., 2015; Dauer et al., 2003). Based on these premises, the present study investigated the effect of STAT4 on neurotoxin MPP+-induced neurotoxicity in SH-SY5Y cells and MPTP-induced neurotoxicity in mouse brains. As previously noticed, STAT4 binds at the promoter of kisspeptin-1 (KISS1) (Jiang et al., 2020). We hypothesized that STAT4 might bind at the promoter of KISS1 and play a critical role in PD pathogenesis. This study might provide useful information on the molecular mechanism of STAT4-meidated KISS1 in PD progression.