Parkinson’s disease is the second most common neurodegenerative disease in the world, with a global prevalence of more than 6 million people, representing a 2.5-fold increase over the prevalence in the previous generation (Dorsey et al., 2018; GBD 2016 Neurology Collaborators., 2019). According to statistics, the incidence of PD in China is increasing, with the number of new patients approaching 100,000 per year. The incidence rate of PD increases with age, and approximately 1% of the world’s elderly (> 60 years) are affected (Tysnes and Storstein, 2017). Among the risk factors for PD, the most important is the age factor. This is followed by genetic factors, with more than 100 genetic risk loci having been identified and characterized (Blauwendraat et al., 2020), while a GWAS has identified nearly 80 different susceptibility loci (Nalls et al., 2019). In addition to these, environmental and behavioral factors have been found to play a role in the pathogenesis of PD (Blauwendraat et al., 2020), primarily associated with pesticide/herbicide exposure, military-related chemicals, and head strikes (Payami et al., 2023). Typical clinical manifestations of PD include motor and non-motor symptoms, including resting tremors, bradykinesia, and postural and gait disturbances, while non-motor symptoms include cognitive and psychiatric abnormalities, sleep disturbances, autonomic dysfunction, and sensory disturbances. These symptoms not only reduce the patient’s quality of life but also represent a burden to the family and society (Foltynie et al., 2024).

The predominant pathological change in PD is the degenerative death of dopaminergic neurons in the substantia nigra of the midbrain, which leads to a significant reduction in dopamine (DA) content in the striatum (caudate nucleus plus pallidum), which impairs its signaling function and thus causes the disease. The pathological markers of PD include α-synuclein (α-syn) and iron loading in the substantia nigra. α-syn is a soluble protein expressed presynaptically and perinuclearly in the central nervous system, which aggregates to form typical inclusion bodies called Lewy bodies. By contrast, iron loading is closely related to the ferroptosis response and is an important mechanism of PD dopaminergic neuronal death (Wang Z. L. et al., 2022).

Despite unprecedented progress in research on the pathogenesis of PD, its etiology remains full of enigmas, and there is currently no effective method for its treatment and prevention, which remain considerable challenges. Combined with extensive experiments, genetic analyses, and pathological autopsies, the possible pathogenesis of PD now focuses on biological themes such as neurosynapses, lysosomes, mitochondria, oxidative stress, ferroptosis, protein aggregation, immune-inflammatory responses, and intestinal ecological dysregulation (Dong-Chen et al., 2023; Ye et al., 2023). Among them, mitochondrial dysfunction, oxidative stress, ferroptosis, and other mechanisms may have a strong relationship with PTEN, which will be covered in detail in this article. In addition, PTEN has a strong genetic association with PD. In the latest PD-associated genetic test (PDGT) (Westenberger et al., 2024) and an observational study called PD GENEration (Cook et al., 2024), among pathogenic genes (e.g., SNCA, LRRK2, VPS35, LRP10, PRKN, PINK1, DJ1), PTEN-induced kinase1 (PINK1 – the classic single gene for PD) remained a high-risk factor for triggering PD. However, there is insufficient information on the correlation between PTEN and factors such as environmental and lifestyle behaviors that trigger PD, which needs to be explored urgently.

Ferroptosis is a novel iron-dependent mode of programmed cell death that occurs in two main ways. The first pathway is a non-enzymatic pathway called the classical Fenton reaction, in which divalent iron reacts with hydrogen peroxide to produce trivalent iron and toxic free radicals. The second pathway is an enzymatic pathway that functions through the action of lipoxygenase (LOX) and cytochrome P450 oxidoreductase (POR). These two pathways continuously generate chain reactions that ultimately allow the oxidation of polysaturated fatty acids (PL-PUFA) in the cell membrane to generate toxic lipid peroxides (PUFA-OOH) (Shen et al., 2018; Dong et al., 2019), which manifest as an accumulation of iron and lipid peroxidation. Interestingly, these toxic lipid peroxides can be reduced back to PL-PUFA by glutathione peroxidase 4 (GPX4). GPX4 functions mainly in the System Xc system (Gao M. et al., 2019), which can be indirectly activated by glutathione (GSH) and is required for the degradation of lipid peroxides (Liu et al., 2022). Recently, Sun et al. (2023) showed that dopaquinone (DAQ) can directly bind to and modify the cysteine residues of GPX4, leading to the loss of dopaminergic neurons in PD. GSH can directly supply cysteine residues to DAQ, and the process of ubiquitination after DAQ modification is mediated by the ubiquitin ligase NEDD4 (Sun et al., 2023), thus refining the mechanism of ferroptosis.

As an iron-dependent chemical response, ferroptosis is closely linked to the transportation and absorption of iron. Abnormalities in serum transferrin (Tf) and its receptor TfR1, such as palmitoylation, have been found to cause neurodegeneration (Park and Chung, 2019). In addition, the overexpression of divalent metal ion transporter 1 (DMT1), an important iron uptake protein, contributes to iron accumulation in the substantia nigra and the loss of dopaminergic neurons (Zhang et al., 2017). Ferroptosis has received increasing attention in recent years. For example, in basic research, Ryan et al., identified iron-loaded microglia as playing a key role in neurodegenerative diseases such as PD (Kenkhuis et al., 2023). In clinical studies, Xia et al. (2021) found that the use of iron-metal grafts in orthopedic surgery should be considered a risk factor for developing PD, adding to the possibility of ferroptosis as a cause of PD. Wang Z. L. et al. (2022) concluded that ferroptosis is likely an important mechanism of dopaminergic neuronal death in PD, as well as a potential target for intervention and treatment.

Recent studies have suggested that PTEN directly regulates ferroptosis. Kezhuo et al. (2022) found that embryonic fibroblasts of PTEN-knockout mice were less sensitive to ferroptosis induced by the ferroptosis inducer Erastin, verifying that PTEN plays a facilitating role in ferroptosis. Glutamate-cysteine ligase modifier subunit (GCLM), which encodes a glutamate and cysteine ligase modifier (Lu, 2009), can inhibit ferroptosis by promoting GSH synthesis (Stockwell et al., 2017). Therefore, when GCLM was knocked down in PTEN-knockout cells, the sensitivity of the cells to Erastin was increased, confirming that the deletion of PTEN could upregulate the expression of GCLM. Therefore, PTEN may inhibit the expression of GCLM, thereby accelerating ferroptosis (Kezhuo et al., 2022). Ferroptosis may be an important reason for PD; however, whether PTEN knockdown or mutation can effectively inhibit the occurrence of ferroptosis and protect against PD remains to be further investigated.

The PAM pathway is mainly composed of three basic components: PI3 kinase (PI3K), protein kinase B (PKB/AKT), and mammalian target of rapamycin-like protein (mTOR) (Figure 2). PI3K belongs to the family of lipid kinases, and full activation of PI3K (class I phosphorylate) converts PIP2 to PIP3, which leads to the recruitment of the serine/threonine kinases AKT and PDK1 near the intracellular membrane. At the same time, the AKT serine 308 site is phosphorylated (Hong-Ju et al., 2010). mTOR is a serine/threonine protein kinase that exists as two complexes, mTORC1 and mTORC2 (Ting and Fu-Sheng, 2016). Activated AKT can trigger mTOR, which interacts with other protein molecules and performs different functions (Li et al., 2022). As a classical oncogenic signaling pathway, dysregulation of the PAM pathway promotes cancer development (Ong et al., 2016; Lee J. H. et al., 2019). For example, in a PI3K-activated xenograft mouse model of breast cancer, inhibition of both ferroptosis and mTORC1 resulted in almost complete tumor regression (Cheng et al., 2022).

Activation of the PAM pathway protects against PD, in which PTEN plays an important role. A recent study by Junmei Y et al., found that sterol regulatory element-binding protein 1 (SREBP1), as a mTORC1-dependent protein regulated by the SREBP1-transcriptional target stearoyl cofactor desaturase-1 (SCD1), can regulate lipid metabolism and exert a ferroptosis-inhibitory effect (Yi et al., 2020), which may protect against PD. The dephosphorylation of PIP3 by PTEN prevents the activation of AKT by PI3K and inhibits the activation of the PAM signaling pathway, reducing its inhibitory effect on ferroptosis, which leads to PD. Activation of the PAM signaling pathway also regulates bypass signaling axes such as Nrf2/HO-1, PKD1, and BDNF/CREB, exerting a protective effect against PD (Gao et al., 2022). Indeed, it was found that rosmarinic acid (RA) promotes antioxidant gene expression by regulating the AKT/Nrf2 signaling pathway to achieve neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced zebrafish PD model, while RA can simultaneously inhibit PTEN expression (Zhao Y. et al., 2020). PTEN-induced kinase 1 (PINK1) was also found to stimulate the physiological effects of neuronal development by activating the PKA-CREB-BDNF signaling axis in a feed-forward loop (Soman et al., 2021).

In addition to the classical Ndfip1-NEDD4 system, many enzymes can mediate PTEN ubiquitination, including WWP1/2, Smurf1/2, CHIP, XIAP, TRIM27/RFP, SPOP, and MKRN-1. The ubiquitination activity of WWP2 on unphosphorylated PTEN even exceeds that of NEDD4 (Chen et al., 2016), while WWP1 inhibits the dimerization and membrane recruitment function of PTEN by polyubiquitination (Lee Y. R. et al., 2019). In terms of sites of action, few studies related to ubiquitination enzymes other than the WWP family have been reported in the nervous system and brain tissue. In terms of disease studies, except for NEDD4, more studies have focused on the tumor inhibitory effects of PTEN, whereas there is almost a gap in the studies on PD.

In addition to ubiquitination, de-ubiquitination, which is a reverse process of ubiquitination, helps maintain protein stability and functionality. Enzymes that mediate PTEN de-ubiquitination include ubiquitin-specific proteases (USP), ovarian tumor proteases (OTU), and so on. The main members of the USP family are USP7 (HAUSP), USP11, USP13, and USP18, whereas the OTU family includes OTUD3. For example, it was found that USP11, which is regulated by FOXO (Park et al., 2019), can act as a regulator of the PTEN/PI3K pathway by deubiquitinating PTEN, thereby enhancing its stability and indirectly inhibiting PI3K signaling (Park et al., 2019). It is presumable that the process continues to inhibit downstream AKT and mTOR signaling and attenuates the inhibition of ferroptosis by the PAM pathway, thereby inducing PD.

Despite progress in this field, there is still vast room for exploration regarding the impact of PTEN on PD occurrence after its involvement in the regulation of ubiquitination.

Mitochondria provide energy for normal neuronal function; therefore, stable mitochondrial function is especially important for nerve cell survival (Devine and Kittler, 2018). Mitochondrial autophagy is a pathway by which cells selectively encapsulate damaged mitochondria and transport them to the lysosome for degradation, thereby maintaining mitochondrial integrity (Lu et al., 2023). Growing evidence suggests that mitochondrial autophagy plays an important role in neurodegenerative diseases such as PD (Barazzuol et al., 2020). Among these, mitochondrial dysfunction (González-Rodríguez et al., 2021) and impaired mitochondrial autophagy (Quinn et al., 2020) are the two main factors contributing to PD. Mitochondrial quality control is an important mechanism that ensures that mitochondrial autophagy can be maintained (Pickles et al., 2018). The human PTEN-inducible putative kinase 1 (PINK1) and Parkin/PRKN are associated with mitochondrial quality control and are a source of regional vulnerability in PD (Ge et al., 2020), of which Parkin is the major causative gene for autosomal recessive juvenile parkinsonism (AR-JP). Mutations in both PINK1 and PRKN can trigger hereditary PD in vivo and in vitro via mitochondrial autophagy (Valente et al., 2004; Han et al., 2023). A recent study found that the combination of heterozygous PRKN and homozygous PTEN-induced PINK1 mutations resulted in earlier PD onset (Song et al., 2023). To address this issue, another study identified a small molecule that activates the PRKN mutant, which cannot be phosphorylated by PINK1, causing the cell to resume mitochondrial autophagy (Sauvé and Gehring, 2024).

Currently, PINK1 and Parkin are the major pathways that mediate mitochondrial autophagy (Harper et al., 2018). Phosphorylated kinase PINK1 recruits PRKN to damaged mitochondria and activates it. PRKN acts as an E3 ubiquitin ligase that ubiquitinates substrates on the surface of mitochondria, degrading them via proteasomes or lysosomes. Promoting the normal progression of dysfunctional mitochondrial autophagy reduces the occurrence of neurodegenerative diseases such as PD. Thus, activating positive regulators such as PINK1 and Parkin or inhibiting negative regulators such as phosphatases and DUBs appears to be necessary to restore impaired mitochondrial autophagy (Li et al., 2023).

Multiple studies have shown that mitochondrial autophagy mechanisms are not consistent across cells. Macroscopically, studies have refined the secondary mechanism by which PINK1 activates PRKN via anterograde feedback, which is responsible for approximately one-quarter of mitochondrial autophagy processes in cells (Fakih et al., 2023). Locally, it has been found that the mitochondrial outer membrane protein Synaptojanin2 (SYNJ2) can transport PINK1 mRNA through an RNA-binding structural domain, thereby supplying distal localized mitochondrial autophagy (Harbauer et al., 2022). To better understand and control the extent of mitochondrial autophagy in cells, many studies have focused on the PINK1–PRKN signaling axis. Because the physiological level of phosphorylated Ub (p-S65-Ub) used to modify mitochondria is very low, one study monitored PINK1–PRKN signaling in tissue cells by developing and characterizing a series of novel p-S65-Ub antibodies (Watzlawik et al., 2024b). Studies have also determined the basal and maximal activation of PINK1 and PRKN using rodent specimens and cells from patients with PD (Watzlawik et al., 2024a), clearly exploring the upper and lower boundaries of the degree of mitochondrial autophagic activity.

In addition, mitochondrial autophagy has been found to be mediated by a variety of substances or accompanied by altered levels of numerous factors, providing a direction for in-depth studies of mitochondrial autophagy. It has been found that mitochondrial autophagy is inhibited in patients with PD with mutations in the GBA (glucosylceramidase beta) gene, which is accompanied by decreased levels of AMBRA1 (Autophagy and beclin 1 regulator 1) (Di Rienzo et al., 2024), although the mechanism is unclear. It has been found that BNIP3L (BCL2/adenovirus E1B interacting protein 3-like) mediates mitochondrial autophagy and thus stimulates mitochondrial remodeling in optic nerve oligodendrocytes (Yazdankhah et al., 2021), providing ideas for the study of PD in the future. Chimeras composed of a mitochondria-targeting sequence (MTS) and ATG16L1-binding peptide (ABP) or LC3-interacting (LIR) have been shown to target and promote mitochondrial autophagy to ameliorate mitochondrial dysfunction in a PD cell model (Mei et al., 2023).

Ribonucleic acid (RNA) is a carrier of genetic information in biological cells. Compared with DNA, RNA has a small molecular weight and highly variable content and has been a hot research topic in the last few years. RNAs are categorized into messenger RNAs and non-coding RNAs according to their structure and function, and non-coding RNAs are divided by size. To date, the known RNAs associated with PTEN and PD are mainly non-coding RNAs, including miRNAs and long-stranded non-coding RNAs (lncRNAs). The main function of miRNAs is to inhibit the expression of target genes and play a role in gene disruption, whereas lncRNAs mainly regulate the transcription, translation, and chromosomal modification of genes (Shaath et al., 2022).

In addition to regulation by RNAs, PTEN transcription is also regulated by several transcription factors. Among the positive regulators, we focus on P53. P53 represses the expression of SLC7A11, a component of System Xc, and also prevents the binding and activation of the NADPH oxidase NOX1 by binding to dipeptidyl peptidase-4 (DPP4), leading to ferroptosis (Jiang et al., 2015), which is associated with PD. P53 can enhance PTEN transcription by binding to its promoter. Meanwhile, PTEN can inhibit the degrading effect of Mdm2 on P53 by inhibiting the PI3K/AKT pathway, and can also enhance the stability of P53 by directly binding to it (Freeman et al., 2003). Among the negative regulators, the SNAIL factor can compete with P53 for binding to the PTEN promoter (Guo et al., 2011). In the PAM pathway, in addition to the classical PI3K/AKT/mTOR signaling pathway, the binding of P53 to PI(4,5)P2 and PI(3,4,5)P3 activates downstream Akt. By contrast, PTEN dephosphorylates PIP3 in the PAM pathway, thereby inhibiting the entire pathway (Chen et al., 2022). It is hypothesized that both P53 and PTEN can affect PD, although their regulatory mechanisms require further exploration.

Several studies have explored transcriptional regulators upstream and downstream of the PTEN signaling axis by inducing PTEN loss, although most of these studies have focused on cancer (Yang et al., 2023). However, such studies have helped to shed light on PTEN and the onset of PD, and most of these studies have investigated the mitochondrial autophagy mechanism. One study reported that XBP1s, a transcription factor that is activated in response to endoplasmic reticulum stress, transactivates PINK1, which triggers endogenous mitochondrial autophagy and thus reduces the occurrence of PD (El Manaa et al., 2021).

In order to function in cells, post-transcriptional PTEN needs to be accurately translated and modified. PTEN is finely regulated by a number of post-translational modifications (PTMs), and while an aberration in this regulation may lead to PTEN inactivation, it also provides an entry point for the study of functional enhancement and reactivation of PTEN (Lee et al., 2018). In addition to phosphorylation and ubiquitination, PTEN has other chemical modifications at the translational level, including SUMOylation, ubiquitination-like, acetylation, oxidation, methylation, and dimerization, to name a few, all of which subliminally regulate the function of PTEN and its role in the PAM signaling pathway (Worby and Dixon, 2014). The mechanisms of PTMs in tumors have been studied more, and mostly revolve around PTEN-induced PINK1 (Ding et al., 2019), but there are fewer related reports in PD. Nevertheless, the activation of PTEN by PTMs can trigger the activation of related kinases. One study found that PTEN can act as an upstream activator of Fyn kinase, leading to the death of dopaminergic neurons and activation of neuroinflammatory pathways, and suggested that PTEN may be a therapeutic target for PD using pharmacological inhibitors of PTEN (Johnson et al., 2023).

If PTEN is mutated, even if PTEN is transcribed and translated correctly, it directly alters the physiological role of PTEN. Regarding PTEN isoforms, studies have identified translational variants of PTEN, including PTENα (PTEN-Long) and PTENβ.

PTENα is translated from an alternative start site upstream of the ATG start sequence and exhibits an addition of 173 amino acids to the standard PTEN. PTENα is a permeable membranous variant and is therefore capable of being secreted from neurons and absorbed by other cells (Putz et al., 2012; Hopkins et al., 2013). PTENα can localize in mitochondria and interact with PTEN, thereby increasing the protein level of PINK1, which regulates mitochondrial function and energy production (Liang et al., 2014). As a protein phosphatase, it allows for the dephosphorylation of phosphorylated ubiquitin (pSer 65-Ub), decreasing its levels. This process counteracts PINK1-mediated ubiquitin phosphorylation, ultimately leading to the blockade of mitochondrial autophagy (Wang et al., 2018). As mitochondrial autophagy has become an important mechanism in the pathogenesis of PD in recent years, using PTENα may be a novel strategy to inhibit PD pathogenesis.

PTENβ is another PTEN isoform that extends at the N-terminus and is manifested by the addition of 148 amino acids to standard PTEN. PTENβ is localized primarily in the nucleolus, where it dephosphorylates nucleolin, thereby negatively regulating the transcription of ribosomal DNA and biotin (Liang et al., 2017). Recent studies have found that the function of ribosomes deteriorates with age, and misfolded protein clumps trigger a “snowball effect” that leads to neurodegenerative diseases, resulting in the development of AD and PD. The reason for this may be the increased load of defective proteins, which disables the protective mechanisms that prevent protein aggregation, providing a new perspective on the study of PTENβ and PD (Stein et al., 2022).

In addition to individual cells, the transport and release of PTEN by exosomes are essential for cell-to-cell communication. Exosomes, small membrane vesicles (30–150 nm) containing complex RNA and proteins, now specifically referred to as discoidal vesicles of 40–100 nm, are the smallest type of extracellular vesicles and were first identified in sheep reticulocytes in 1983. In recent years, exosomes have received increased attention from researchers because of their potential role in the diagnosis and treatment of diseases (Kenkhuis et al., 2023).

Exosomes are involved in the pathogenesis of PD. Using autopsies of patients with PD, Braak et al. (2003) found that the distribution of α-syn can be shifted from one cell to another. This process can be mediated by several mechanisms of cellular release and uptake, among which translocation by exosomes is an important one (Valdinocci et al., 2017). Different cell types in the human brain can release exosomes, including neurons, astrocytes, and microglia. It has been demonstrated that neurons overexpressing α-syn can release and transfer α-syn to other normal neurons via exosomes (Alvarez-Erviti et al., 2011). Astrocyte-derived exosomes have also been shown to induce protein aggregation in the mouse brain (Dinkins et al., 2014). Recently, it was found that CD11 + exosomes isolated from the CSF of patients with PD contained α-syn in vivo and that exosomes in microglia were able to induce nigrostriatal degeneration and promote the delivery of α-syn in PD cells (Guo et al., 2020). Taken together, these findings show that exosomes function as a “transit station” in PD, and if their transporter function can be inhibited, it may be possible to indirectly prevent the progression of PD.

Phosphatase and tension homolog is also closely linked to exosomes and can be jointly involved in the regulation of PD. Recent evidence has shown that PTEN is ubiquitinated by Ndfip1 and NEDD4 at the lysine 13 site, which enables it to be secreted in exosomes and taken up by other cells (Kim et al., 2018). PTEN can also be secreted from exosomes to exert extracellular phosphatase activity (Ge et al., 2020), promoting lysosomal biogenesis and acidification. For example, it has been found that PTEN dephosphorylates transcription factor EB (TFEB) at Ser211, and defects in PTEN lead to decreased lysosomal-mediated degradation of multivesicular vesicles and increased secretion of exosomes, which promote the proliferation and invasion of cholangiocarcinoma (CCA) (Jiang et al., 2023). However, some studies on TBI have found that TBI may better activate the PAM pathway and induce ferroptosis, thereby worsening PD, with exosomes playing a role similar to the one they play in CCA. TBI can induce ferroptosis, as evidenced by increased ACSL4 expression and decreased expression of GPX4 (Wang D. et al., 2022), and this process can be reversed by exocytosis. However, exosomes can further promote the expression of PINK1 and Parkin after the occurrence of TBI (Zhang et al., 2023), which mediates ubiquitination, drives mitochondrial autophagy, and accomplishes the protective effect on PD neuronal cells (Goiran et al., 2022). Whether exosomes promote PD pathogenesis or inhibit PD progression remains to be further explored.