Parkinson's disease (PD) primarily affects the substantia nigra (SN) and striatum strata, causing progressive deterioration of both motor and non-motor functions (Savitt et al., 2006). Symptoms include resting tremors, unstable gait, balance problems, autonomic nerve dysfunction, cognitive impairments, and sleep disturbances (Balestrino and Schapira, 2020; Emre et al., 2007; Jankovic, 2008; Reichmann et al., 2016). Loss of dopaminergic neurons in the SN and striatum leads to dopamine deficiency, which can be attributed to decreased expression of key factors such as tyrosine hydroxylase (TH) and nuclear receptor related 1 (Nurr1) (Al-Nusaif et al., 2022; J and K, 1998; Kadkhodaei et al., 2009; Nagatsu et al., 2022). On the other hand, loss and degeneration of nerve cells lead to a decrease in microtubule-associated protein 2 (MAP2) and class III beta-tubulin (Tuj1) expression (Cossette et al., 2005). Currently, rodents are widely used as animal models for PD, but their cognitive abilities and social behaviors are limited, which affects the disease characteristics and pathological manifestations (Mustapha and Taib, 2021). In contrast, cynomolgus monkeys are better suited for mimicking human PD than rodents due to their similarity with human beings in nervous system structure and function, pathology and physiology, typical motor symptoms post 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure, and complex social behavior and cognitive abilities, which make them trustworthy for evaluating the efficacy and safety of new treatments (Emborg, 2007; Harding, 2017; Masilamoni and Smith, 2018; Simola et al., 2007; Zeng et al., 2018).

Currently, it is primarily treated with dopamine agonists that is commonly used in clinical trials, which only reduce motor symptoms and are virtually ineffective for non-motor symptoms (Emborg, 2007; Poewe, 2009). Tolerance develops with long-term use, and side effects such as nausea, vomiting, hypotension, and mental anomalies become noticeable (Emborg, 2007; Alonso Cánovas et al., 2014; Fabbrini et al., 2007). When the drug's effect is diminished, symptoms reoccur, and an dose reincrease may result in motor problems such as drug-resistant tremors, attention deficit and hyperactivity disorder (ADHD), and spasticity (Iravani et al., 2012; Raza et al., 2019; Wood, 2010). Therefore, it's crucial to develop new treatments. Neural stem cells (NSCs) are a type of cell with self-renewal and pluripotent differentiation characteristics promoting tissue regeneration and repair, which is significant for PD patients with damaged brain regions (Deisseroth et al., 2004; Gage, 2000; Hsieh and Schneider, 2013). Thus, it is seen as a potential treatment for neurological diseases.

The brain's energy requirements are exceedingly high, and mitochondria, as a source of energy supply, is critical for sustaining proper brain and nerve cell activity (Gasparotto et al., 2022; Hitze et al., 2010). Impairment of mitochondrial function can result in cell damage and death, which can lead to neuraldegenerative disorders (Gao et al., 2022). The main features of mitochondrial morphology and dysfunction in PD are decreased adenosine triphosphate (ATP) synthesis, increased reactive oxygen species (ROS), autophagy, and mtDNA mutations, decreased de novo biogenesis of mitochondria, and mitochondrial dynamics disorders (Golpich et al., 2016; Legati and Ghezzi, 2023; Olagunju et al., 2023; Wang et al., 2019). When the mitochondrial membrane potential decreases, ATP synthesis will decrease or even stop, leading to insufficiency of nerve cells, alteration of excitability, and disruption of synaptic transmission, hence nerve cell death (Hill et al., 2020; Luo et al., 2020). The main cause of reactive oxygen species (ROS) accumulation in the SN of PD is the decrease of mitochondrial complex I, leading to dopamine nerve cell damage (Chinta and Andersen, 2008; Ghahari et al., 2020; Ryu et al., 2013). Mitochondrial fusion/fission, autophagy, and biogenesis all work together to regulate mitochondrial quality. Damaged mitochondria can fuse with healthy mitochondria, providing an improved energy supply and preserving normal mitochondrial function. Maintaining the balance of mitochondrial fusion/fission, biogenesis, and autophagy is crucial for the function of nerve cells (Ge et al., 2020; Lim et al., 2012; Park et al., 2018). Nevertheless, the cause of PD's mitochondrial damage remains elusive. Currently, there are no drugs targeting mitochondrial therapy in PD patients, so NSCs may improve mitochondrial dysfunction at the source. However, it is unclear whether and to what extend NSCs are related with mitochondria in MPTP-induced PD cynomolgus.

In this study, we established a stable MPTP-induced PD model in cynomolgus monkeys and clarified that the ability of NSCs to mediate mitochondria contributed to the treatment of PD.