Neurological illnesses are characterised by the gradual degeneration and death of neurons in the central and peripheral nervous systems, impairing memory and motor functions in the brain (Trevarrow et al., 2023; Giri et al., 2024). Globally, people are suffering from neurological disorders (Schiess et al., 2024), such as Huntington's disease (HD) (Mehan et al., 2017), Multiple sclerosis(MS) (Khan et al., 2023), Amyotrophic lateral sclerosis (ALS) (Minj et al., 2021), Parkinson's disease (PD) (Yadav et al., 2017; Alharbi et al., 2022), and Alzheimer's disease (AD) (Duggal et al., 2020). In these neurological illnesses, neural system functionality was diminished due to the loss of neuronal or glial cells, including ataxia, dementia, amnesia, bradykinesia, blindness, and paralysis (Hyeon et al., 2023).

The cell signaling pathway modulates the brain's physiological and pathological processes (Sahu et al., 2021). It is vital for neurotransmitter release, receptor activation, and intracellular reactions, enabling synaptic transmission and plasticity, which are fundamental for cognitive tasks, including learning and memory (Berridge, 2014). Excessive activation of these signaling systems may result in disease development, and dysregulated signaling pathways are associated with neurodegenerative disorders (Mancini et al., 2023) (Pathak et al., 2022).

The glial cell line-derived neurotrophic factor (GDNF) is a protein that promotes the survival and differentiation of dopaminergic neurons in humans(Rai and Singh, 2020). The survival and maintenance of dopaminergic and motor neurons are crucial, as they prevent cell death during development and damage and are necessary for the healing of the central and peripheral nervous systems(Rai et al., 2016). The lack of GDNF has considerable consequences, particularly in neurodegenerative disorders (Sun et al., 2020) (Azevedo et al., 2020) (Mathew et al., 2023).

The GDNF family receptor alpha-1 (GFRα1) is a glycosylphosphatidylinositol (GPI) attached to cell surface receptors (Runeberg-Roos and Penn, 2020). This receptor is critical in dendritic growth and synaptogenesis in hippocampal pyramidal neurons during early postnatal development (Bonafina et al., 2019). It is found on the surface of the neuronal Schwann cells and is released in a soluble form (Avenel et al., 2024). Dysfunction of this receptor may result in aberrant neuronal development, potentially contributing to illnesses such as autism spectrum disorders and intellectual impairments (Jiang et al., 2022a).

Rearranged during transfection (RET) is the tyrosine kinase receptor, which interacts with ligands at the cell surface and mediates various essential roles in a variety of cellular processes such as proliferation, differentiation, survival, migration, and metabolism (Tomuleasa et al., 2024). This receptor participates in multiple signaling pathways essential for neuronal function, and its malfunction may result in numerous neurological diseases (Conway et al., 2020).

AKT, also called protein kinase B, is a serine /threonine-specific protein kinase involved in glucose transport and cell proliferation, survival, and apoptosis, among other biological functions (Gao et al., 2014a). Three highly homologous isoforms of AKT, specifically AKT1, AKT2, and AKT3, often referred to as PKBa, PKBb, and PKBg, are all genomically encoded and expressed by mammalian cells (Brand et al., 2015). Akt1 is significantly expressed in the adult brain, AKT2 is predominantly found in astrocytes within the cortex and hippocampus, and AKT3 is crucial for neuronal formation, influencing processes such as dendritic patterning and axonal development. (Lee et al., 2014) (Palumbo et al., 2021)(Lopes et al., 2019).

Extracellular signal-regulated kinases (ERK) represent an essential signaling pathway that controls cell growth, differentiation, and apoptosis (Sahu et al., 2021). Two members, ERK-1 and ERK-2, possess nearly identical amino acid sequences; ERK-1 comprises 378 amino acid residues, whereas ERK-2 contains 360 amino acid residues (Bahar et al., 2023). Abnormal activation of ERK1/2 in various neurological disorders has been implicated in epilepsy, schizophrenia, and neurodegenerative diseases (Korotkov et al., 2017).

Glycogen synthase kinase-3 beta (GSK3β) is a multifunctional protein kinase, having several phosphorylation sites situated at the SerThr residues, specifically at the fourth amino acid from the C-terminal, serving as a priming mechanism (Krishnankutty et al., 2017). Ubiquitous expression of GSK3β is found in all tissues and cells but is most prevalent in the brain (Krishnankutty et al., 2017). GSK3β controls diverse biological activities, such as gene expression, cellular architecture, neuronal development, plasticity, cell survival, and proliferation (Alsadat et al., 2021; Abbah et al., 2022). This review analyzes the GDNF/GFRA1/RET signaling pathway's role in neuronal survival and protection in neurodegenerative disorders. It highlights the interplay of pathways like AKT, ERK1/2, and GSK3β, suggesting modulation could enhance treatments.

GDNF is the first member of the GDNF family of dimeric ligands (GFL), which also includes neurturin (NRTN) (Zihlmann et al., 2005), artemin (ARTN) (Lee and Song, 2013), persephin (PSPN) (Iwasaki et al., 2023), and GDF15 (Mullican et al., 2017). GFLs form receptor-associated transmembrane complexes with cognate GFRα co-receptors, including GDNF-GFRα1 (Barrenschee et al., 2017), NTN-GFRα2 (Wan et al., 2011), ARTN-GFRα3 (Hou et al., 2021), PSPN-GFRα4 (Mahato and Sidorova, 2020a), and GDF15-GFRAL(Alexopoulou et al., 2023). The GFRα family comprises two subtypes: one featuring two or three exterior cysteine-rich helical domains (D1–3), a flexible C-tail (CT), and several transmembrane proteins identified as GFRAL (Wang et al., 2006; Parkash et al., 2008). A GFL-GFRα complex comprises one GFL molecule that associates with two GFRα molecules (GFL2-GFRα2), resulting in a U-shaped structure characterised by various degrees of hinge bending (Parkash and Goldman, 2009; Sandmark et al., 2018). GDNF2-GFRα12 is an extracellular signaling protein that engages with the RET receptor tyrosine kinase at the cell membrane, facilitating neuronal growth, migration, differentiation, and survival (Ledda et al., 2008).

Neuronal synapses form connections throughout a highly organized and dynamic process at the target tissues and neurons (Südhof, 2021). Synaptic adhesion molecules (SAMs) are located in transport vesicles at the postsynaptic membrane and growth cones at the presynaptic terminal, and they can be classified as homophilic (protocadherins, synCAMs) or heterophilic (neurexin-neuroligin) (Dalva et al., 2007; Wang and Wenthold, 2009). trans-Synaptic adhesion molecules are categorised into three types: the receptor protein tyrosine phosphatase (R-PTP) superfamily, the recently designated adherent protocadherins, and the ligand-dependent cell adhesion molecules (LiCAMs) (Ledda, 2007; Ledda et al., 2007). Cerebellin engages with presynaptic neurexin and postsynaptic GluD, neurotrophin-3 associates with postsynaptic TrkC7 and presynaptic PTPσ7, whereas GDNF attaches to both pre and postsynaptic GFRα1 (Ammendrup-Johnsen et al., 2015).

GDNF also belongs to the group of neurotrophic factors that play the highest role in the sustaining and differentiation of dopaminergic neurons in the mesencephalon, as it is involved in the development of such as PD (Mesa-Infante et al., 2022). FCE is believed to safeguard spinal motor neurons and engage in signaling pathways that enhance neuronal health and development (Zhang et al., 2023). Upon binding of GDNF to its receptor GFRA1, RET tyrosine kinase is activated, initiating intracellular signaling that enhances neuronal survival (Kim and Kim, 2018; Cintrón-Colón et al., 2020). GDNF is also involved in regulating the nigrostriatal pathway, which governs motor coordination, and has been linked to neurotrophic factors that might be used as medications in ALS and PD (de Luis and Pascual, 2016; Bale and Doshi, 2023).

GFRA1 is a GDNF binding site and mediates the GDNF signal (Zajzon et al., 2013). It is mainly synthesized in neurons but can be found in some nonneuronal cells (Uesaka et al., 2013). Researchers believe that active interactions between GDNF and GFRA1 are essential for appropriate neuronal circuit development (Yoo et al., 2024). Deregulating the GFRA1 gene can significantly impact neuronal survival and lead to neurodevelopmental complications (Li et al., 2022b). In developmental contexts, GFRA1 is crucial for migrating enteric neuron precursors, indicating its role in forming the enteric nervous system (Boesmans et al., 2022). Its expression patterns vary across developmental stages, more widespread in neonatal than in adults, suggesting a dynamic role in neuronal development and plasticity (Bonsi et al., 2022).

GFRα1 is involved in neuronal survival and synaptic adhesion because it is a co-receptor of GDNF (Konishi et al., 2014). GDNF establishes an interaction with GFRα1, a receptor tyrosine kinase receptor of the RET type (Paratcha and Ledda, 2008). This, consequently, aids in the development of signaling, which is crucial for the brain's functionality (Theparambil et al., 2024). New studies have described the structural behavior of the GDNF-GFRα1 complex (Bonafina et al., 2018). X-ray crystallography and electron microscopy identified that GFRα1 and GDNF formed a decametric complex that consists of two pentameric GFRα1 and five GDNF molecules (Adams et al., 2021). The GDNF-GFRα1 connection is reported to have essential tasks for RET activation and neural synaptic adhesion (Mikroulis et al., 2022).

Consequently, GDNF must bind to GFRα1 to communicate with RET with excellent binding capability (Houghton et al., 2023). This complex stimulates RET activation through homodimerization with subsequent autophosphorylation and Akt and Erk3 intracellular signaling (Winter et al., 2011). It's signal, especially if RET is low or absent (Ibáñez et al., 2020). The present GFRα1 is also known as a ligand-dependent cell adhesion molecule (LiCAM) (Ledda, 2007). This can cause trans-homophilic binding between the cell and its nearest neighbours, enhancing cell adhesion without RET (Omar et al., 2022). This function is particularly crucial in neurons when RET is not expressed, facilitating the preservation of synapse differentiation. (Walmod et al., 2007) (Golden et al., 2010) (Cohen et al., 2022).

The GDNF-GFRα1 signaling pathway possesses significant therapeutic potential, particularly in neurodegenerative disorders like PD(Ivanova et al., 2018). Stimulation of this system appears to have beneficial neurologic effects and may enhance neuronal preservation (Blanco-Duque et al., 2024). GDNF/GFRα1 interactions can be targeted to enhance glioblastoma chemotherapy results (Avenel et al., 2024). The figure summarizes several mandatory signaling beneficial in neuroprotection involving GDNF, ARTN, NRTN, and PSPN ligands to protect and encourage neurons to live (Fig. 1). (See Table 1.)

RET is a transmembrane receptor tyrosine kinase, showing four cadherin-like motifs and 16 cystines in 120 amino acids (Ibáñez, 2013). Activation of RET involves the binding of Ca2+ ions to cadherin-like domains, the interaction of GFL with glycosyl phosphatidylinositol-anchored co-receptor GFL receptor α (GFRα1–4), a molecular event wherein two RET receptors dimerise at the molecular level, followed by autophosphorylation on multiple tyrosine residues in the cytoplasm (Li et al., 2019a). Tyrosine residues in the cytoplasm of the RET protein facilitate the retention and interaction with other adaptor proteins, hence extending signal transduction and activating other pathways such as PI3K/AKT, RAS/MAPK/ERK, JAK2/STAT3, and PLC γ (Guo et al., 2024).

The RET-Y687 can interact with SHP2 phosphatase and promote activation of the PI3K/AKT; therefore, cellular survival is promoted (Perrinjaquet et al., 2010). Additionally, there is the phosphorylation of RET at Y905, which increases the stability of the active conformation of RET and is needed for contact with adaptor proteins Grb7/10 (Balogh et al., 2010; Balogh et al., 2012), whereas RET-Y981 is necessary for the interaction and loading of the kinase Src (Plaza-Menacho et al., 2016). PLC-γ also interacts with Y1015 phosphorylated RET and leads to the activation of PKC (Gao et al., 2013). The substrate RET-Y1062 phosphorylation binds to several adaptor proteins required for PI3K/AKT, RAS/RAF/MEK/ERK, and MAPK (Gedaly et al., 2012). Lastly, Grb2 binds with phosphorylated RET at the Y1096 location, serving as a secondary site via which RET can activate the RAS/RAF/MEK/ERK signaling cascade, facilitating cell proliferation and differentiation (Prazeres et al., 2011; Wen et al., 2024).

Akt is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs); subsequently, active Akt phosphorylates and activates one or more subtypes of class I PI3Ks on the plasma membrane (Vanhaesebroeck et al., 2010). Consequently, active PI3K was utilized to phosphorylate the T ring and the C hydrophobic motif inside the Akt activation core domain of Akt1, together with the corresponding residues of Akt2 and Akt3 (Plotz et al., 2020; Han et al., 2024; Tian et al., 2024). Furthermore, IGF1 stimulates Akt; when IGF1 binds to IGF1R, it attracts IRS-1 and PI3K, activating both (Yoshida and Delafontaine, 2020). When PI3K is activated, PIP3 is produced, which influences phosphoinositide-dependent kinase-1, PDK1, and Akt (Levina et al., 2022). TRAF6 and TBK1 are both involved in the control of Akt (Wang et al., 2018b). MAPKs exist in two categories: conventional or typical; these are ERK1/2, p38α/β/γ/δ, JNK1/2/3, and ERK5, while the atypical MAPKs include ERK3 (Cuadrado and Nebreda, 2010; Yáñez-Gómez et al., 2023). It is known that activation of the RAS-RAF-MEK-ERK1/2 signal is revealed in numerous brilliant articles that explain the mechanism of the action of the signal (Cargnello and Roux, 2012; Fisher and Larkin, 2012). It is activated by receptor protein kinases on the cell surface, such as EGFR, PDGFR, VEGFR, and GPCRs, in response to growth and differentiation stimuli, mitogens, cytokines, and GPCR ligands (Rudd, 2005; Mandal et al., 2014). This activated receptor activates downstream molecules, including the GRB2, that bind with SOS, a guanine nucleotide exchange factor (Tong et al., 2021; Martinez and Sudhamsu, 2023). This positions the cytosolic protein SOS adjacent to the membrane-bound, GDP-bound, inactive RAS GTPase (also called RAS) (Kolch et al., 2023).

SOS causes a transitory rearrangement of the RAS and substitutes the GDP with a GTP molecule, activating it (Miyakawa et al., 2012; Tu et al., 2012). This makes many other executives of the RAF kinase bend the cell's plasma membrane and actuate through homo- or heterodimerization (Poulikakos and Rosen, 2011). Consequently, they activate the dual specificity MEK1/2 kinases (hereafter termed MEK kinase), which subsequently activates ERK1/2 via the dual phosphorylation of the TEY motif in the activation loop of the ERK/1 kinase subdomain (Roberts and Der, 2007; Dai et al., 2011).

The ERK1/ 2 cascade path is one of the major signaling pathways to mitigate two huge transmembrane signals (Vetterkind et al., 2013). Their corresponding cellular responses by phosphorylation or other activates several downstream targets, including Cyclin D1 (Kong et al., 2019). Its prototyped targets include c-Jun, c-Fos, ATF-2, Elk-1, RSK1–3, MNK1/2, Bcl-2, and Topo IIb (Lucas et al., 2022). It can also activate cells via kinase activity alongside other targets, such as phosphorylates and signaling pathways to regulate cellular stress responses, gene transcription activation, cell division, apoptosis and survival, gene turnover rates, cell motility, migration, invasiveness, metastasis, and cell-matrix interactions (Thévenod and Lee, 2013; Kaduwal et al., 2015; Tsuboi et al., 2017; Shang et al., 2024). The diagram illustrates the various signaling channels through which neurons interact with neurotoxic stress to counteract and enhance understanding of neuroprotection processes (Fig. 2).

These pathways, including RET/AKT/GSK3β, are essential for neurogenic defense, specifically in neurodegenerative diseases (Xiong et al., 2024). The systems are fundamentally based on RET, a receptor tyrosine kinase, which dimerises and autophosphorylates upon binding to neurotrophic factors, such as GDNF (Perrinjaquet et al., 2010; Kakati et al., 2023). This activation allows the recruitment of signaling molecules needed for downstream signaling (McAnally et al., 2017). Constitutive activation of RET subsequently stimulates phosphoinositide 3-kinase (PI3K), which phosphorylates phosphoinositide 4,5-bisphosphate (PIP2) to produce phosphoinositide 3,4,5-trisphosphate (PIP3) (Karmacharya et al., 2009). An accumulation of PIP3 at this plasma membrane is essential for AKT recruitment and activation (Badolia, 2012; Kearney et al., 2021; Barth et al., 2022). Upon incorporation into the membrane, AKT is activated by phosphorylation by PDK1 (3-phosphoinositide-dependent protein kinase 1) and an additional kinase (Kampa et al., 2012; Di Blasio et al., 2017; Jiang et al., 2022b). After becoming activated, AKT plays an important role in acting as an intermediary of this pathway in neuroprotection (Barrio et al., 2021). Therefore, one of the activities is phosphorylation and consequential inhibition of GSK3β (Glycogen synthase kinase 3 beta) that results in cell killing and death of neurons (Venè et al., 2014). AKT inactivation of GSK3β has suppresses its pro-apoptotic signals through serine phosphorylation, hence augmenting neuronal resilience and safeguarding against stressors, oxidative stress, and excitotoxicity (Liu et al., 2020). This relationship not only enhances cell survival but also facilitates neurogenesis and neuronal differentiation, all of which are essential for overall neuronal health and repair (Jeon et al., 2012; Ramakrishna et al., 2023).

Akt is the primary downstream molecule of PI3K; when engaged, it produces PIP3, which activates AKT (Glaviano et al., 2023). PIP3 interacts with both AKT and PDK1, which stimulates AKT phosphorylation at Thr308 (He et al., 2021). Although phosphorylation of Ser 473 is not essential for the kinase's base kinase function, complete activation necessitates phosphorylation of Ser473 by mTORC2 (Vadlakonda et al., 2013). Deregulated AKT affects downstream proteins like Bad, Caspase 9, NF κ B, and GSK 3 β (Jaiswal et al., 2019). This modification influences fundamental cellular functions and initiates a series of actions; AKT diminishes pro-apoptotic proteins like Bad and Bax while elevating anti-apoptotic proteins such as Bcl-2 and Mcl-1, so establishing a balance between survival and apoptosis (Yilmaz et al., 2023).

Protein phosphorylation and cell cycle regulation, particularly in the G1/S phase, inactivate inhibitory proteins such as p27^Kip1 and p21^Cip1, allowing cells to cycle and proliferate (Vadlakonda et al., 2013). The AKT/GSK3β signaling pathway promotes cell survival, proliferation, and metabolic control (Liu et al., 2018). AKT activation promotes cell survival and proliferation by inhibiting Caspase and Bcl-2 proteins, increasing glucose absorption, and inactivating GSK 3β (Vadlakonda et al., 2013). Abnormalities in this route result in a variety of illnesses, including cancer, neurological disorders, and metabolic diseases (Liu and Lin, 2019).

RET can activate the PI3K/AKT pathway by binding to the p85 subunit of PI3K, which is the regulatory subunit of this kinase (Shi et al., 2019). When AKT is phosphorylated, GSK3β activity increases, influencing neuronal development and function (Ruvolo et al., 2015). GSK3β is another kinase that can phosphate RET and thus change the signal produced by RET (Phukan et al., 2010). This crosstalk allows bridging extrinsic factors (e.g., GDNF) (Zhang et al., 2020). Transgenic AD models show lower RET expression and overactivation of GSK3β molecules (Rodríguez-Matellán et al., 2020).

Focussing on this neural pathway may have therapeutic implications for nervous system disorders, including neurodegeneration and neuropsychiatric conditions (Zhang et al., 2023). The RET receptor and PI3K/AKT/GSK3β signaling pathways are integral to cerebral functions (Xue et al., 2021). This interaction is critical for proper brain growth and function, and anything that disrupts it is linked to various neurological illnesses (Kitagishi et al., 2012). Specific processes may mediate such interactions, and a greater understanding of the mechanisms generating these interactions may lead to the development of novel therapeutics for brain illnesses (Razani et al., 2021). The neuroprotection diagram mainly includes the PI3K/AKT pathway, of which neurogenesis plays a crucial role (Gong et al., 2023). The figure also shows other signaling pathways involved in neuronal survival and anti-apoptosis (Fig. 3).

GDNF binds to the GFRα1 receptor, forming a complex that, upon sufficient activation, triggers the RET receptor and is essential for various intracellular signaling pathways, particularly those regulating cell survival and proliferation mediated by AKT and ERK (Yang and Han, 2010; Park and Bolton, 2015; Li et al., 2022a). Nonetheless, several findings suggest that GFRα1 can modify RET signaling in a biassed fashion (Houghton et al., 2023). GFRα1 can modulate the cellular signaling regarding GDNF by promoting or inhibiting the AKT and ERK pathways depending on the environment (Li et al., 2022a). Autophosphorylated RET increases subsequent components, specifically GDNF-GFRα1, while AKT (Ser473) phosphorylates upstream of RET. Downstream, RET increases ERK phosphorylation, which enhances neuronal survival and differentiation (Boscia et al., 2009; Latteyer et al., 2016; Wills et al., 2017). Moreover, it has been demonstrated that GDNF can affect its target cells through any of the RET-associated mechanisms and other receptors, for instance, the neuronal cell adhesion molecules (NCAM) (Azevedo et al., 2020). This method is engaged in many other biological processes apart from this one, such as how cells stick or relocate (Khalili and Ahmad, 2015).

The RET receptor is linked to AKT signaling, which has a cytoprotective influence on the cell and binds it to manage its metabolism (Mahato and Sidorova, 2020b). These have a mutual interaction on the cytoprotective activity in neurons (Nosi et al., 2021). It is essential to recognise the significance of these signaling relationships in formulating therapeutic strategies for neurodegenerative illnesses (Dong-Chen et al., 2023). For example, small molecules that bind to RET have also been utilized to initiate such pathways in models of retinal degeneration, restoring neuronal death (Yang et al., 2024). Consequently, the investigation identified the subsequent signaling pathway: GDNF/GFRα1/RET exhibits neuroprotective properties against degeneration (Hauck et al., 2006). The arrangement of this phenomenon was hypothesized during multiple studies due to the augmented protection of neurons under stress, whether oxidative or damaging. In animal models of RP, the same class of drugs that ‘sensitised’ RET improved neuroprotective functions and diminished cell death, thereby emphasising the significance of this mechanism (Kantharaj et al., 2022) (Jo et al., 2017).

The activation of the RET receptor triggers significant phosphorylation of proteins essential for cell viability (Schalm et al., 2010; Hyeon et al., 2023). For example, activation of RET raises the phosphorylated AKT amount (Li et al., 2015; Talukder et al., 2024). In turn, cell survival pathways and metabolic processes in more cells than just the cancerous cells would be stimulated (Tomuleasa et al., 2024). Previous studies indicate that GDNF demonstrates clinical efficacy for these neurons in animal models of neurodegenerative diseases, including Parkinson's disease, via enhancing neuronal health and this signaling mechanism (Chengcheng et al., 2024).

In addition to neuronal survival, GDNF/GFRα1/RET signaling activates events related to neurite growth and synaptogenesis (Sidorova et al., 2017). This occurs by activating alternative signal transduction pathways, such as MAPK and fAK, which are pivotal in developing dendrites and spines in neurons (Shi et al., 2009). In hippocampal neurons, GDNF interacting with NCAM1 has been shown to upregulate dendritic growth, amplifying the pathway's significance on neuronal cabling and functionality (Mikroulis et al., 2022). In situations of stress, such as ischemia or glutamate excitotoxicity, GDNF provides even more neuroprotection (Belov Kirdajova et al., 2020; Magdaleno Roman and Chapa González, 2024; Martínez-Torres and Morán, 2024). For instance, it has been observed that GDNF may protect hippocampal neurons from oxygen-glucose deprivation by enhancing RET accumulation, hence diminishing neuronal apoptotic death (Abadpour et al., 2017; Li W et al., 2019c). During brain ischemia, the levels of GDNF and its receptors may be altered to reduce effectiveness (Curcio et al., 2015). However, during transient ischemia, specific receptor isoforms like RET51 expression may be reduced, but the presence of GDNF still protects neurons due to the activation of other receptors (Curcio et al., 2015). Understanding the long-term preservation of the GDNF signaling system may facilitate therapeutic interventions for neurodegenerative illnesses (Runeberg-Roos and Penn, 2020). Small-molecule RET agonists should actuate this signaling system to promote neuronal survival and function in its affected populations (Jmaeff et al., 2020). This mechanism may be utilized to govern strategies for reversing neuronal degradation associated with diseases such as PD and other neurodegenerative disorders (Prakash et al., 2014; Kasanga et al., 2023).

The GDNF/GFRα1/RET signaling is significant to neuroprotection and neurodevelopment processes in the mammal CNS (Wang et al., 2022). GDNF promotes neuronal survival and differentiation by interacting with the RET receptor through GFRα1, concurrently activating downstream signaling pathways, including Akt and Erk (Conway et al., 2020). This signaling also assists in preserving the identity of neurons and is also necessary for activities such as neurite outgrowth and synapse formation (Pekarek et al., 2022). This recognised pathway may contribute to the onset of neurodegenerative diseases, highlighting the essential roles of the cells, tissues, and genetic products implicated in the intricate processes of neuronal maintenance, differentiation, and regeneration during development and post-injury (García-Revilla et al., 2022). This figure summarizes numerous necessary signals useful in neuroprotection, reflecting a significant focus on how neurons can be saved and supported (Fig. 4).

The pathophysiology of the major neurological disorders, including PD (Lin et al., 2024), AD (Mehan et al., 2011), ALS (Mòdol-Caballero et al., 2021), and MS (Noori et al., 2020), requires an understanding of the GDNF, its receptors GFRA1 and RET, and such intracellular signal transduction molecules as AKT, ERK1/2, and GSK3β (Romorini et al., 2016). GDNF is also involved in the survival and maintenance of dopaminergic neurons, particularly in the substantia nigra, whose deficiency has been implicated in PD (Kramer and Liss, 2015). The binding of GDNF to GFRA1 induces the activation of the HEP-RET receptor and, therefore, intracellular signaling pathways that include AKT and ERK1/2 and that enhance neuronal survival, growth, and repair (Bonanomi et al., 2012). Prolonged activation of GSK3β, typically resulting from pathogenic stress, negates the recovery functions of AKT and ERK1/2, hence enhancing apoptosis and neuroinflammation (Liu et al., 2020). The accumulation of amyloid-β and tau protein phosphorylated by GSK3β in Alzheimer's disease may result in diminished synaptic function and neuronal survival (Zhou et al., 2022).

In addition, such cellular signaling defects might enhance the production of toxic substances and cytokines that promote neuronal death in a self-reinforcing cycle (Zhao et al., 2021). Consequently, experimental and clinical targeting of the GDNF-GFRA1-RET signaling pathway and its downstream effectors presents interesting strategies for therapeutic interventions aimed at alleviating or curing these severe disorders (Kasanga et al., 2023)(Spires-Jones et al., 2017).

The GDNF receptor and its complex, comprising GFRA1, RET, and downstream pathways involving AKT, ERK1/2, and GSK3-beta, are essential for neuronal survival, functionality, and neuroprotection, particularly in PD(Mesa-Infante et al., 2022), ALS (Baloh et al., 2022), HD (McBride et al., 2006), AD (Airavaara et al., 2011), and MS (Jmaeff et al., 2020). The neurotrophic effects of GDNF are realized through its binding to the co-receptor, GFRA1, which, together with RET, forms a receptor complex (Ibáñez et al., 2020). RET engages a network of intracellular signaling pathways by which the activation of AKT and ERK1/2 kinases are essential for cell survival and proliferation (Chen et al., 2021). Upon activation, the AKT pathway inhibits the synthesis of pro-apoptotic molecules (Das et al., 2016). It generally supports cell survival by inactivating GSK3-beta, the kinase implicated in neurodegenerative diseases through phosphorylation (Thornton et al., 2018).

Elevated activated GSK3-beta levels induce tau pathology and neuroinflammation, as observed in AD, whereas GSK3-beta inhibition by AKT provides neuroprotection (Yang et al., 2020). A further aspect of RET signaling encompasses the ERK1/2 pathway, which is associated with neuronal development, axonal growth, and synaptic function, all of which are essential for learning and memory (Chen et al., 2022). These networks interact and coordinate neurotrophic signaling; for instance, upon stimulation, RET signals both AKT survival and ERK1/2 differentiation outcomes (Ishii et al., 2021).

GDNF and its receptor system have also been tested in clinical trials in PD patients by different extents of efficacy, though more often limited by their delivery across the blood-brain barrier (Whone et al., 2019). Altered RET signal transduction and probable dysregulation of downstream Akt/GSK3-β or ERK pathways in synaptic dysfunction and neurodegeneration have been identified in studies (Ma et al., 2007). Modulating these pathways with either GDNF mimetics or small molecule inhibitors can address the neurotrophic deficits, reduce apoptosis, and enhance neuronal survival in numerous neurodegenerative diseases (Tansey et al., 2021). The figure shows the major molecular events postulated to play a role in neurodegenerative illnesses, with a particular focus on cell survival, inflammatory processes, and protein aggregation (Fig. 5).

Fig. 6 shows interactions of various biochemical signaling pathways associated with different neuropsychiatric disorders with different molecular changes resulting in neurodegeneration, inflammation, and oxidative stress (Fig. 6).

Pharmacological regulation of GDNF/GFRA1/RET/AKT/ERK1/2/GSK3-beta signaling pathways should enhance the neuroprotection and neuronal survival in different neurodegenerative diseases, including PD and AD (Di Liberto et al., 2011; Trautmann et al., 2017). Prolonged GDNF delivery using (AAV vectors) and small chemical activators of RET receptors to stimulate AKT and ERK1/2 pathway are essential for cell survival and neural regeneration (Yang and Han, 2010). Also, GSK3-beta inhibitors have clinical potential in reducing the tau pathology in AD (Abadio et al., 2015). These medicines try to address the problem of these circuits to develop more enhanced treatments for neurodegenerative diseases (Bido et al., 2021).

There are multiple interesting therapeutic prospects and treatment strategies for neurodegenerative diseases that involve the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3-beta signaling (Li et al., 2022b; Nouri et al., 2024). GDNF gene therapy using AAV vectors and encapsulated cell biodelivery devices is planned to encourage sustainable GDNF release in the brain and enhance neuron survival (Wahlberg et al., 2020;). Small molecule RET agonists like BT13, try to stimulate the RET signaling and thus promote neuroprotection without injecting GDNF (Mahato et al., 2020). Tideglusib and LY2090314 are other GSK3-beta inhibitors used to reduce tau progression in cases of AD (Hua et al., 2023). Further, a few drugs of the AKT/ERK pathway are under trial for cell survival and to save neurons in the hope of treating neurodegenerative diseases (El Ouaamari et al., 2023).

Targeting the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3β signaling pathways presents several challenges in the pursuit of effective neuroprotection. One significant hurdle is the efficient delivery of GDNF to the brain, as the blood-brain barrier limits access to therapeutic agents. While direct infusion methods have shown limited success, emerging strategies such as gene therapy using viral vectors (e.g., AAV) and encapsulated cell bio delivery systems offer promising alternatives. However, these methods require further optimization to achieve safe and long-lasting delivery without adverse effects.

Another challenge is managing off-target effects associated with the RET receptor and its downstream pathways. Persistent activation of these signals could disrupt cellular homeostasis, potentially leading to tumorigenesis or immune disorders. Therefore, it is essential to identify selective small-molecule activators that can precisely stimulate desired neuroprotective pathways while minimizing unintended consequences.

Moreover, the interplay between these pathways necessitates careful regulation. Overactivation of AKT while inhibiting GSK3β can lead to metabolic and immune disturbances. Future research should focus on developing targeted precision interventions, such as allosteric modulators that specifically activate RET receptor agonists. Additionally, determining optimal dosing regimens and timing for therapeutic interventions is crucial for maximizing neuroprotection while minimizing side effects.

In conclusion, advancing understanding and application of these pathways through innovative drug delivery systems and precision drug development could enhance therapeutic outcomes in treating neurodegenerative diseases. Continued research in this arena holds the promise of improving patient outcomes and quality of life for individuals afflicted by conditions such as AD,PD,MS,ALS.