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The aim of our study was to show the presence of neurotrophic factors in breast milk that have a significant impact on neurocognitive development of children aged two years and beyond. Mothers expressed at least 5 mL of breast milk into sterile containers when their children 18, 24, and ≥ 25 months of age, and then specimens were transferred to Eppendorf tubes and stored at -20 °C. One day before the analysis, specimens were kept at +4 °C and then thawed at room temperature to prepare them for analysis. Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and S100B neurotrophic growth factor levels were analyzed using the sandwich enzyme-linked immunosorbent assay (ELISA) principles. Sixty-two mothers with children aged 18 months were included in the study. The mean age of the mothers was 33.4 (± 0.71) years. Due to the detection limits of the commercial kits, BDNF and S100B analyses could not be conducted. Therefore, only GDNF was analyzed. The presence of GDNF was found in the breast milk samples taken at 18, 24, and ≥ 25 months, and the median (min max) values were 315,505 ng/mL (193,067 750,718), 316,721 ng/mL (161,278 l-752,252), and 564,577 ng/mL (238,528-781,104) respectively. There were no significant differences between GDNF levels of breast milk samples collected from the same mother at the three different time points (18, 24, and ≥ 25 months) (p = 0.278). Conclusion: Our study was the first to show the presence of neurotrophic factors in the breast milk of mothers with healthy children over one year of age. Our results provide evidence-based data on the importance of breastfeeding until children are at least two years of age. What is Known: • Presence of Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and S100B neurotrophic growth factor have been shown in the breast milk of mothers whose infants are the first year of life. What is New: • Glial Cell Line-Derived Neurotrophic factors continue to present in breast milk of mothers with children aged 18, 24, and ≥ 25 months, without any significant difference in level between months. [ABSTRACT FROM AUTHOR]

Purpose: Stem cell therapy offers a promising solution for congenital diseases like Hirschsprung's disease (HSCR). Optimizing stem cell efficacy by modifying the cells and their environment is crucial, but in vitro culture conditions need to be further improved. Glial cell-derived neurotrophic factor (GDNF) plays an important role in neuronal survival, proliferation, migration and differentiation during enteric nervous system (ENS) development. In this study, the effects of GDNF on neurites derived from an Ednrb knockout model were investigated with the aim of enhancing the neurogenic potential of enteric neural crest cells (ENCCs). Methods: Neurospheres were generated form Ednrb+/+ (control) and Ednrb−/− mice at embryonic day13.5 (E13.5) with Sox10-green fluorescent protein (Venus) transgenic expression. These neurospheres were cultured in control media and neurospheres from Ednrb−/− were cultured with either control media or media supplemented with GDNF. ENCCs differentiation was assessed using immunofluorescence staining after 18 days. Results: GDNF-treated Ednrb−/− neurospheres showed increased size and higher density of Sox10-positive ENCCs compared to untreated Ednrb−/− neurospheres. GDNF also enhanced the distribution of both TUJ1-positive neurons and S100-positive glial cells. Conclusion: GDNF effectively enhanced the neurogenic potential of ENCCs from HSCR animal model. This finding is crucial for the development of cell therapy in HSCR. [ABSTRACT FROM AUTHOR]

Patients with systemic lupus erythematosus (SLE) are known to frequently suffer from comorbid cardiovascular diseases (CVDs). There are abundant data on cytokine levels and their role in the pathogenesis of SLE, while growth factors have received much less attention. The aim of this study was to analyze growth factor levels in SLE patients and their association with the presence of comorbid CVDs. The serum concentrations for the granulocyte-macrophage colony-stimulating factor (GM-CSF), nerve growth factor β (NGFβ), glial cell line-derived neurotrophic factor (GDNF), and neuregulin-1 β (NRG-1β) were determined in the SLE patients (n = 35) and healthy individuals (n = 38) by a Luminex multiplex assay. The NGFβ and NRG-1β concentrations were shown to be significantly higher in the total group of SLE patients (median [Q1–Q3]: 3.6 [1.3–4.5] and 52.5 [8.5–148], respectively) compared with the healthy individuals (2.9 [1.3–3.4] and 13.7 [4.4–42] ng/mL, respectively). The GM-CSF and GDNF levels did not differ. Interestingly, elevated NRG-1β levels were associated with the presence of CVDs, as SLE patients with CVDs had significantly higher NRG-1β levels (99 [22–242]) compared with the controls (13.7 [4.4–42]) and patients without CVDs (19 [9–80] ng/mL). The model for the binary classification of SLE patients with and without CVDs based on the NRG-1β level had an average predictive ability (AUC = 0.67). Thus, altered levels of growth factors may be associated with comorbid CVDs in SLE patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by immune-mediated inflammation and neurodegeneration in the central nervous system (CNS). In this study; we aimed to investigate the gene expression and plasma protein levels of three neuroprotective genes—heat shock proteins (HSP90 and HSP60) and glial cell line-derived neurotrophic factor (GDNF)—in MS patients compared to healthy controls. Forty patients with relapsing-remitting MS and 40 healthy volunteers participated in this study. Gene expression was measured using reverse transcription quantitative real-time PCR, and protein levels were assessed via ELISA. The results showed a significant increase in HSP90 (1.7-fold) and HSP60 (2-fold) gene expression in MS patients compared to controls, along with corresponding increases in protein levels (1.5-fold for both HSP90 and HSP60). In contrast, GDNF gene expression and protein levels were significantly reduced in MS patients, with a 7-fold decrease in gene expression and a 1.6-fold reduction in protein levels. Notably, a non-linear relationship between GDNF gene expression and protein concentration was observed in MS patients, suggesting complex regulatory mechanisms influencing GDNF in the disease. The upregulation of HSP90 and HSP60 in MS highlights their roles in immune regulation and stress responses, while the reduction in GDNF indicates impaired neuroprotection. These findings suggest that HSP90, HSP60, and GDNF could serve as biomarkers for disease progression and as potential therapeutic targets in MS, offering promising avenues for future research and treatment development.

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our previous work strongly supported the essential role of the avian ceca, present at the junction of the midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds led to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) is highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS.

In this study, the effects of different combinations of the genes Vegf, Ang, and Gdnf injected both using direct virus-mediated injection (adenovirus, Ad5) and umbilical cord blood mononuclear cells (UCBCs) on the processes of stimulation of post-ischemic innervation, angiogenesis, and regeneration in skeletal muscle were investigated in a rat hindlimb chronic ischemia model. It was shown that more pronounced stimulation of angiogenesis and restoration of post-ischemic innervation were achieved both in the early (28 days post-ischemia, dpi) and late (42 dpi) terms of the experiment in the calf muscle when UCBCs delivered the combination of Ad5-Vegf and Ad5-Ang compared to the direct injection of the same vector combination into the area of ischemia. At the same time, the inclusion of Ad5-Gdnf in the combination of Ad5-Vegf and Ad5-Ang directly injected or administered by UCBCs provided a significant increase in the number of centronuclear muscle fibers, indicating stimulation of post-ischemic reparative myogenesis. This study allowed us to determine the most effective gene combinations for angiogenesis and neurogenesis, which, in the future, may serve as the basis for the development of gene and gene cell products for the treatment of chronic lower limb ischemia.

Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development. [ABSTRACT FROM AUTHOR]

Introduction: Suicide represents a significant public health problem whose neurobiology is not yet fully understood. In many cases, suicidal behavior and psychiatric spectrum disorders are linked, in particular, to major depression. An emerging pathophysiological hypothesis underlines the role of neurotrophic factors, proteins involved in neurogenesis, in synaptic plasticity in response to stressors. Our research aims to evaluate the degree of expression of brain neurotrophic factor (BDNF) in brain areas involved in depressive disorder in suicidal subjects. Furthermore, we want to evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) in suicidal subjects. Methods: We selected twenty confirmed cases of suicide among subjects with a clinical history of depressive pathology and possible psychopharmacological treatment, compared to ten controls of individuals who died of non-suicidal causes. For all selected cases and controls, immunohistochemical investigations were performed using a panel of antibodies against the BDNF and GDNF antigens on samples from the various brain areas. Results and discussion: The results show that BDNF was under-expressed in the cerebral parenchyma of subjects who died by suicide compared to controls, while there was an overexpression of GDNF in suicide victims, these data could be useful for a clinical application as potentialmarkers for suicidal risk, to assess the severity of depression and development of specific pharmacological therapies for depression. [ABSTRACT FROM AUTHOR]

Both of exosomes derived from mesenchymal stem cells (MSCs) and glial cell line-derived neurotrophic factor (GDNF) show potential for the treatment of neuropathic pain. Here, the analgesic effects of exosomes derived from bone marrow MSCs (BMSCs) were investigated. BMSCs-derived exosomes were isolated and characterized. Chronic constriction injury (CCI) was constructed to induce neuropathic pain in rats, which were then treated with exosomes. Pain behaviors were evaluated by measuring paw withdrawal thresholds and latency. The changes of key proteins, including cytokines, were explored using Western blot and ELISA. Administration of BMSCs-derived exosomes alleviated neuropathic pain, as demonstrated by the decrease of thermal hyperalgesia and mechanical allodynia, as well as the reduced secretion of pro-inflammatory cytokines in CCI rats. These effects were comparable to the treatment of GDNF alone. Mechanically, the exosomes suppressed the CCI-induced activation of TLR2/MyD88/NF-κB signaling pathway, while GDNF knockdown impaired their analgesic effects on CCI rat. BMSCs-derived exosomes may alleviate CCI-induced neuropathic pain and inflammation in rats by transporting GDNF. [ABSTRACT FROM AUTHOR]

Objective: Gene therapy by convection‐enhanced delivery of type 2 adeno‐associated virus‐glial cell derived neurotrophic factor (AAV2‐GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). Methods: A 63‐year‐old man with advanced PD received AAV2‐GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F‐Fluorodopa (18F‐FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2‐GDNF infusion. Results: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2‐GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F‐DOPA‐PET scanning. Putaminal regions responded as expected to AAV2‐GDNF. Conclusion: After AAV2‐GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F‐FDOPA‐PET signal, suggesting the regenerative potential of AAV2‐GDNF in PD. [ABSTRACT FROM AUTHOR]

Hereditary neurodegenerative diseases (hNDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and others are primarily characterized by their progressive nature, severely compromising both the cognitive and motor abilities of patients. The underlying genetic component in hNDDs contributes to disease risk, creating a complex genetic landscape. Considering the fact that growth factors play crucial roles in regulating cellular processes, such as proliferation, differentiation, and survival, they could have therapeutic potential for hNDDs, provided appropriate dosing and safe delivery approaches are ensured. This article presents a detailed overview of growth factors, and explores their therapeutic potential in treating hNDDs, emphasizing their roles in neuronal survival, growth, and synaptic plasticity. However, challenges such as proper dosing, delivery methods, and patient variability can hinder their clinical application. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions. [ABSTRACT FROM AUTHOR]

IntroductionVolumetric muscle loss (VML) is one of the most severe and debilitating conditions in orthopedic and regenerative medicine. Current treatment modalities often fail to restore the normal structure and function of the damaged skeletal muscle. Bioengineered tissue constructs using the patient’s own cells have emerged as a promising alternative treatment option, showing positive outcomes in fostering new muscle tissue formation. However, achieving timely and proper innervation of the implanted muscle constructs remains a significant challenge. In this study, we present a clinically relevant strategy aimed at enhancing and sustaining the natural regenerative response of peripheral nerves to accelerate the innervation of biofabricated skeletal muscle implants.MethodsWe previously developed a controlled-release neurotrophic factor delivery system using poly (lactic-co-glycolic acid) (PLGA) microspheres encapsulating ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF). Here, we incorporate this neurotrophic factor delivery system into bioprinted muscle constructs to facilitate innervation in vivo.ResultsOur results demonstrate that the neurotrophic factors released from the microspheres provide a chemical cue, significantly enhancing the neurite sprouting and functional innervation of the muscle cells in the biofabricated muscle construct within 12 weeks post-implantation.DiscussionOur approach provides a clinically applicable treatment option for VML through accelerated innervation of biomanufactured muscle implants and subsequent improvements in functionality.

Objective: To investigate the effects of shumian capsules combined with agomelatine tablets on polysomnography characteristics and serum 5-hydroxytryptamine (5-HT), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in patients with depression and insomnia. Methods: 94 patients with depression and insomnia who were divided into study group (treated with agomelatine tablets and shumian capsules) and control group (treated with agomelatine tablets) according to the random number table method, 47 cases in each group. The Hamilton Depression Scale-17 (HAMD-17), Pittsburgh Sleep Quality Index (PSQI), Fatigue Scale (FS-14) scale score, 5-HT, BDNF, GDNF, polysomnography (PSG) related indicators [total sleep time (TST), sleep efficiency (SE), non-rapid eye movement sleep 1, 2, 3 (NREM1, NREM2, NREM3)] were compared between two groups. Results: Compared with control group after treatment, the scores of HAMD-17, PSQI and FS-14 in study group were relatively lower (P<0.05). Compared with control group after treatment, 5-HT, BDNF and GDNF in study group were relatively higher (P<0.05). Compared with control group after treatment, TST, SE, NREM1, NREM2 and NREM3 in study group were relatively higher (P<0.05). Conclusion: Patients with depression and insomnia are treat with agomelatine tablets and shumian capsules, the symptoms of insomnia and depression are significantly improve, which may be relate to the improvement of serum 5-HT, BDNF and GDNF levels. [ABSTRACT FROM AUTHOR]

Glial cell line-derived neurotrophic factor (GDNF) is among the strongest dopamine neuron function- and survival-promoting factors known. Due to this reason, it has clinical relevance in dopamine disorders such as Parkinson's disease and schizophrenia. In the striatum, GDNF is exclusively expressed in interneurons, which make up only about 0.6% of striatal cells. Despite clinical significance, histological analysis of striatal GDNF system arborization and relevance to incoming dopamine axons, which bear its receptor RET, has remained enigmatic. This is mainly due to the lack of antibodies able to visualize GDNF- and RET-positive cellular processes; here, we overcome this problem by using knock-in marker alleles. We find that GDNF neurons chemoattract RET+ axons at least seven times farther in distance than medium spiny neurons (MSNs), which make up 95% of striatal neurons. Furthermore, we provide evidence that tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is enriched towards GDNF neurons in the dopamine axons. Finally, we find that GDNF neuron arborizations occupy approximately only twelve times less striatal volume than 135 times more abundant MSNs. Collectively, our results improve our understanding of how endogenous GDNF affects striatal dopamine system function. [ABSTRACT FROM AUTHOR]

Motor functional improvement represents a paramount treatment objective in the post-spinal cord injury (SCI) recovery process. However, neuronal cell death and axonal degeneration following SCI disrupt neural signaling, impeding the motor functional recovery. In this study, we developed a multifunctional decellularized spinal cord-derived extracellular matrix (dSECM), crosslinked with glial cell-derived neurotrophic factor (GDNF), to promote differentiation of stem cells into neural-like cells and facilitate axonogenesis and remyelination. After decellularization, the immunogenic cellular components were effectively removed in dSECM, while the crucial protein components were retained which supports stem cells proliferation and differentiation. Furthermore, sustained release of GDNF from the dSECM facilitated axonogenesis and remyelination by activating the PI3K/Akt and MEK/Erk pathways. Our findings demonstrate that the dSECM-GDNF platform promotes neurogenesis, axonogenesis, and remyelination to enhance neural signaling, thereby yielding promising therapeutic effects for motor functional improvement after SCI. The dSECM promotes the proliferation and differentiation of MSCs or NSCs by retaining proteins associated with positive regulation of neurogenesis and neuronal differentiation, while eliminating proteins related to negative regulation of neurogenesis. After crosslinking, GDNF can be gradually released from the platform, thereby promoting neural differentiation, axonogenesis, and remyelination to enhance neural signaling through activation of the PI3K/Akt and MEK/Erk pathways. In vivo experiments demonstrated that dSECM-GDNF/MSC@GelMA hydrogel exhibited the ability to facilitate neuronal regeneration at 4 weeks post-surgery, while promoting axonogenesis and remyelination at 8 weeks post-surgery, ultimately leading to enhanced motor functional recovery. This study elucidates the ability of neural regeneration strategy to promote motor functional recovery and provides a promising approach for designing multifunctional tissue for SCI treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors. Methods: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 10 6 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF). Results: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05. Conclusions: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results. [ABSTRACT FROM AUTHOR]

Aim: Schizophrenia involves complex interactions between biological and environmental factors, including childhood trauma, cognitive impairments, and premorbid adjustment. Predicting its severity and progression remains challenging. Biomarkers like glial cell line-derived neurotrophic factor (GDNF) and miRNA-29a may bridge biological and environmental aspects. The goal was to explore the connections between miRNAs and neural proteins and cognitive functioning, childhood trauma, and premorbid adjustment in the first episode of psychosis (FEP). Method: This study included 19 FEP patients who underwent clinical evaluation with: the Childhood Trauma Questionnaire (CTQ), the Premorbid Adjustment Scale (PAS), the Positive and Negative Syndrome Scale (PANSS), and the Montreal Cognitive Assessment Scale (MoCA). Multiplex assays for plasma proteins were conducted with Luminex xMAP technology. Additionally, miRNA levels were quantitatively determined through RNA extraction, cDNA synthesis, and RT- qPCR on a 7500 Fast Real-Time PCR System. Results: Among miRNAs, only miR-29a-3p exhibited a significant correlation with PAS-C scores (r = -0.513, p = 0.025) and cognitive improvement (r = -0.505, p = 0.033). Among the analyzed proteins, only GDNF showed correlations with MoCA scores at the baseline and after 3 months (r = 0.533, p = 0.0189 and r = 0.598, p = 0.007), cognitive improvement (r = 0.511, p = 0.025), and CTQ subtests. MIF concentrations correlated with the PAS-C subscale (r = -0.5670, p = 0.011). Conclusion: GDNF and miR-29a-3p are promising as biomarkers for understanding and addressing cognitive deficits in psychosis. This study links miRNA and MIF to premorbid adjustment and reveals GDNF's unique role in connection with childhood trauma. [ABSTRACT FROM AUTHOR]

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs’ response to peripheral nerve injury.

IntroductionParkinson’s disease (PD) presents a significant challenge in medical science, as current treatments are limited to symptom management and often carry significant side effects. Our study introduces an innovative approach to evaluate the effects of gdnf overexpression mediated by CRISPRa in an in vitro model of Parkinson’s disease. The expression of gdnf can have neuroprotective effects, being related to the modulation of neuroinflammation and pathways associated with cell survival, differentiation, and growth.MethodsWe have developed a targeted delivery system using a magnetite nanostructured vehicle for the efficient transport of genetic material. This system has resulted in a substantial increase, up to 200-fold) in gdnf expression in an In vitro model of Parkinson’s disease using a mixed primary culture of astrocytes, neurons, and microglia.Results and DiscussionThe delivery system exhibits significant endosomal escape of more than 56%, crucial for the effective delivery and activation of the genetic material within cells. The increased gdnf expression correlates with a notable reduction in MAO-B complex activity, reaching basal values of 14.8 μU/μg of protein, and a reduction in reactive oxygen species. Additionally, there is up to a 34.6% increase in cell viability in an In vitro Parkinson’s disease model treated with the neurotoxin MPTP. Our study shows that increasing gdnf expression can remediate some of the cellular symptoms associated with Parkinson’s disease in an in vitro model of the disease using a novel nanostructured delivery system.

Introduction: Suicide represents a significant public health problem whose neurobiology is not yet fully understood. In many cases, suicidal behavior and psychiatric spectrum disorders are linked, in particular, to major depression. An emerging pathophysiological hypothesis underlines the role of neurotrophic factors, proteins involved in neurogenesis, in synaptic plasticity in response to stressors. Our research aims to evaluate the degree of expression of brain neurotrophic factor (BDNF) in brain areas involved in depressive disorder in suicidal subjects. Furthermore, we want to evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) in suicidal subjects.Methods: We selected twenty confirmed cases of suicide among subjects with a clinical history of depressive pathology and possible psychopharmacological treatment, compared to ten controls of individuals who died of non-suicidal causes. For all selected cases and controls, immunohistochemical investigations were performed using a panel of antibodies against the BDNF and GDNF antigens on samples from the various brain areas.Results and discussion: The results show that BDNF was under-expressed in the cerebral parenchyma of subjects who died by suicide compared to controls, while there was an overexpression of GDNF in suicide victims, these data could be useful for a clinical application as potential markers for suicidal risk, to assess the severity of depression and development of specific pharmacological therapies for depression.

The RET receptor tyrosine kinase plays a pivotal role in cell survival, proliferation, and differentiation, and its abnormal activation leads to cancers through receptor fusions or point mutations. Mutations that disrupt the disulfide network in the extracellular domain (ECD) of RET drive multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome associated with the development of thyroid cancers. However, structural details of how specific mutations affect RET are unclear. Here, we present the first structural insights into the ECD of the RET(C634R) mutant, the most common mutation in MEN2A. Using electron microscopy, we demonstrate that the C634R mutation causes ligand-independent dimerization of the RET ECD, revealing an unusual tail-to-tail conformation that is distinct from the ligand-induced signaling dimer of WT RET. Additionally, we show that the RETC634R ECD dimer can form complexes with at least two of the canonical RET ligands and that these complexes form very different structures than WT RET ECD upon ligand binding. In conclusion, this structural analysis of cysteine-mutant RET ECD suggests a potential key mechanism of cancer induction in MEN2A, both in the absence and presence of its native ligands, and may offer new targets for therapeutic intervention.

Background and Purpose: Parkinson’s disease is a progressive neurological disorder, where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) is one of the most important neurotrophins that regenerates dopaminergic neurons by Rearranged during transfection (RET) receptor tyrosine kinase in Parkinson's disease. The effect of exercise on these proteins are not well known. Therefore, the present study was conducted to examine the effect of high intensity swimming training on GDNF and RET gene expression in hippocampal tissue in rats with Parkinson's disease. Material and Methods: In this experimental and pure study, twenty-one male Wistar rats (age 8 to 10 weeks and weight 200-250 gr) were purchased from the Animal Breeding Center of Islamic Azad University, Shiraz branch and transferred to the animal laboratory of this university. Parkinson's disease was induced in fourteen rats by injection of 1 mg/kg reserpine during 5 days. Thereafter, they were randomly divided into Parkinson's disease group or Parkinson’s disease + training group. The rats in the training group performed 6 weeks of high intensity interval swimming including 20 repetitions of 30 seconds swimming followed by 30 seconds rest. Moreover, seven remaining rats received no intervention and were allocated into the healthy control group. GDNF and RET gene expressions were measured in hippocampus 48h after the last training session, using Real Time-PCR. Data were analyzed by using one-way ANOVA test and Bonferoni’s post-hoc. Data were analyzed by using SPSS22 at the P

Background: To investigate the expression levels and diagnostic value of glial cell line-derived neurotrophic factor (GDNF), carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) in patients with colorectal carcinoma (CRC). Methods: 50 CRC patients at our hospital from Feb. 2020 to Feb. 2021 were chosen as the malignant group, another 50 patients with benign colonic diseases were chosen as the benign group, and 50 healthy people who came to our hospital for physical examination during the same period were considered as the control group. Fasting peripheral venous blood was taken from all research subjects in the morning and tested by a fully-automated electrochemiluminometer to determine the GDNF, CEA and CA199 levels. The sensitivity and specificity of the combined detection of the three indexes for CRC were analyzed, and the receiver operating characteristic (ROC) curve was plotted to record the area under the curve (AUC). Results: The malignant group had remarkably higher CEA and CA199 levels (P

Aim: Aberrations in brain connections are implicated in the pathogenesis of Parkinson's disease (PD). We previously demonstrated that Glial cell‐derived neurotrophic factor (GDNF) reduction is associated with cognition decline. Nonetheless, it is elusive if the pattern of brain topological connectivity differed across PD with divergent serum GDNF levels, and the accompanying profile of cognitive deficits has yet to be determined. Methods: We collected data on the participants' cognition, demographics, and serum GDNF levels. Participants underwent 3.0T magnetic resonance imaging, and we assessed the degree centrality, brain network topology, and cortical thickness of the healthy control (HC) (n = 25), PD‐high‐GDNF (n = 19), and PD‐low‐GDNF (n = 19) groups using graph‐theoretic measures of resting‐state functional MRI to reveal how much brain connectivity varies and its clinical correlates, as well as to determine factors predicting the cognitive status in PD. Results: The results show different network properties between groups. Degree centrality abnormalities were found in the right inferior frontal gyrus and right parietal lobe postcentral gyrus, linked with cognition scores. The two aberrant clusters serve as a potentially powerful signal for determining whether a patient has PD and the patient's cognition level after integrating with GDNF, duration, and dopamine dosage. Moreover, we found a significant positive relationship between the thickness of the left caudal middle frontal lobe and a plethora of cognitive domains. Further discriminant analysis revealed that the cortical thickness of this region could distinguish PD patients from healthy controls. The mental state evaluation will also be more precise when paired with GDNF and duration. Conclusion: Our findings reveal that the topological features of brain networks and cortical thickness are altered in PD patients with cognitive deficits. The above change, accompanied by the serum GDNF, may have merit as a diagnosis marker for PD and, arguably, cognition status. [ABSTRACT FROM AUTHOR]

Germ cell transplantation (GCT) is a promising biotechnology that enables the production of donor-derived gametes in surrogate recipients. It plays a crucial role in the protection of endangered species, the propagation of elite species with desired traits, and long-term preservation of genetic resources. This significance is particularly pronounced when GCT is synergistically employed with cryopreservation techniques. However, GCT often encounters challenges due to low colonization rates and, in some cases, complete loss of donor cells in recipients. Glial cell line-derived neurotrophic factor (GDNF) plays a pivotal role in sustaining the self-renewal of spermatogonial stem cells (SSCs) in mammals. Additionally, it has been shown to promote the proliferation of spermatogonia in vitro cultures in certain animal species. In turbot (Scophthalmus maximus), we found that the expressions of gdnf and gfrα1a were predominantly observed in spermatogonia rather than somatic cells, which differed from their expression patterns in mammals. The efficiency of exogenous spermatogonia transplantation in Japanese flounder (Paralichthys olivaceus) larvae could be substantially enhanced by incubating donor cells from turbot with 100 ng/ml GDNF prior to transplantation. This led to a noteworthy increase in the colonization rate, rising from 33%-50%–61.5%. Additionally, the addition of 20 ng/ml GDNF in cell medium could also promote the proliferation of turbot germ cells in vitro. These results demonstrated the gdnf in turbot testis expression characteristics and suggested that addition of GNDF could be an effective way to improve the GCT efficiency and promote the germ cells expansion during in vitro culture. • Expression patterns of gdnf and gfrα1a in turbot reveal preferential localization in spermatogonia, distinct from mammas. • GDNF incubation significantly enhances exogenous spermatogonia transplantation efficiency in Japanese flounder larvae. • GDNF addition boosts turbot germ cell proliferation in culture, hinting its potential to enhance germ cell expansion in vitro. [ABSTRACT FROM AUTHOR]

Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson's disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF's ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor α-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson's disease. [ABSTRACT FROM AUTHOR]

Our previous study showed that glial-derived neurotrophic factor (GDNF) expression is upregulated in asthmatic human lungs, and GDNF regulates calcium responses through its receptor GDNF family receptor a1 (GFRa1) and RET receptor in human airway smooth muscle (ASM) cells. In this study, we tested the hypothesis that airway GDNF contributes to airway hyperreactivity (AHR) and remodeling using a mixed allergen mouse model. Adult C57BL/6J mice were intranasally exposed to mixed allergens (ovalbumin, Aspergillus, Alternaria, house dust mite) over 4 wk with concurrent exposure to recombinant GDNF, or extracellular GDNF chelator GFRa1-Fc. Airway resistance and compliance to methacholine were assessed using FlexiVent. Lung expression of GDNF, GFRa1, RET, collagen, and fibronectin was examined by RT-PCR and histology staining. Allergen exposure increased GDNF expression in bronchial airways including ASM and epithelium. Laser capture microdissection of the ASM layer showed increased mRNA for GDNF, GFRa1, and RET in allergen-treated mice. Allergen exposure increased protein expression of GDNF and RET, but not GFRa1, in ASM. Intranasal administration of GDNF enhanced baseline responses to methacholine but did not consistently potentiate allergen effects. GDNF also induced airway thickening, and collagen deposition in bronchial airways. Chelation of GDNF by GFRa1-Fc attenuated allergen-induced AHR and particularly remodeling. These data suggest that locally produced GDNF, potentially derived from epithelium and/or ASM, contributes to AHR and remodeling relevant to asthma. NEW & NOTEWORTHY Local production of growth factors within the airway with autocrine/paracrine effects can promote features of asthma. Here, we show that glial-derived neurotrophic factor (GDNF) is a procontractile and proremodeling factor that contributes to allergen-induced airway hyperreactivity and tissue remodeling in a mouse model of asthma. Blocking GDNF signaling attenuates allergen-induced airway hyperreactivity and remodeling, suggesting a novel approach to alleviating structural and functional changes in the asthmatic airway. [ABSTRACT FROM AUTHOR]

Background and Purpose: Parkinson's disease is a progressive neurological disorder, where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) is one of the most important neurotrophins that regenerates dopaminergic neurons by Rearranged during transfection (RET) receptor tyrosine kinase in Parkinson's disease. The effect of exercise on these proteins are not well known. Therefore, the present study was conducted to examine the effect of high intensity swimming training on GDNF and RET gene expression in hippocampal tissue in rats with Parkinson's disease. Materials and Methods: In this experimental and pure study, twenty-one male Wistar rats (age 8 to 10 weeks and weight 200-250 gr) were purchased from the Animal Breeding Center of Islamic Azad University, Shiraz branch and transferred to the animal laboratory of this university. Parkinson's disease was induced in fourteen rats by injection of 1 mg/kg reserpine during 5 days. Thereafter, they were randomly divided into Parkinson's disease group or Parkinson's disease + training group. The rats in the training group performed 6 weeks of high intensity interval swimming including 20 repetitions of 30 seconds swimming followed by 30 seconds rest. Moreover, seven remaining rats received no intervention and were allocated into the healthy control group. GDNF and RET gene expressions were measured in hippocampus 48h after the last training session, using Real Time-PCR. Data were analyzed by using one-way ANOVA test and Bonferoni's post-hoc. Data were analyzed by using SPSS22 at the P<0.05.. Results: Data analyzes revealed that GDNF and RET gene expression were reduced after induction of Parkinson's disease compared to the healthy control group (P=0.001, P=0.03, respectively). After 6 weeks of training, GDNF and RET gene expressions were increased compared to the Parkinson's disease group (P=0.009, and P=0.007, respectively), whereas, no significant differences were observed between training group and healthy control group (P=0.6 and P=0.9. respectively). Conclusion: In general, it seems that high-intensity interval swimming training used in this study could improve dopaminergic neuron survival in Parkinson's disease by increasing GDNF as a neurotrophine factor and subsequent signaling receptor tyrosine kinase RET. Since, the available data are scars in this field, future studies specially in human are needed. [ABSTRACT FROM AUTHOR]

AimSchizophrenia involves complex interactions between biological and environmental factors, including childhood trauma, cognitive impairments, and premorbid adjustment. Predicting its severity and progression remains challenging. Biomarkers like glial cell line-derived neurotrophic factor (GDNF) and miRNA-29a may bridge biological and environmental aspects. The goal was to explore the connections between miRNAs and neural proteins and cognitive functioning, childhood trauma, and premorbid adjustment in the first episode of psychosis (FEP).MethodThis study included 19 FEP patients who underwent clinical evaluation with: the Childhood Trauma Questionnaire (CTQ), the Premorbid Adjustment Scale (PAS), the Positive and Negative Syndrome Scale (PANSS), and the Montreal Cognitive Assessment Scale (MoCA). Multiplex assays for plasma proteins were conducted with Luminex xMAP technology. Additionally, miRNA levels were quantitatively determined through RNA extraction, cDNA synthesis, and RT-qPCR on a 7500 Fast Real-Time PCR System.ResultsAmong miRNAs, only miR-29a-3p exhibited a significant correlation with PAS-C scores (r = -0.513, p = 0.025) and cognitive improvement (r = -0.505, p = 0.033). Among the analyzed proteins, only GDNF showed correlations with MoCA scores at the baseline and after 3 months (r = 0.533, p = 0.0189 and r = 0.598, p = 0.007), cognitive improvement (r = 0.511, p = 0.025), and CTQ subtests. MIF concentrations correlated with the PAS-C subscale (r = -0.5670, p = 0.011).ConclusionGDNF and miR-29a-3p are promising as biomarkers for understanding and addressing cognitive deficits in psychosis. This study links miRNA and MIF to premorbid adjustment and reveals GDNF’s unique role in connection with childhood trauma.

Abstract Background Testosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression. Methods The human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin–eosin staining and immunohistochemistry. Results Testosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm. Conclusion Testosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation. Graphical Abstract The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.

Hereditary neurodegenerative diseases (hNDDs) such as Alzheimer’s, Parkinson’s, Huntington’s disease, and others are primarily characterized by their progressive nature, severely compromising both the cognitive and motor abilities of patients. The underlying genetic component in hNDDs contributes to disease risk, creating a complex genetic landscape. Considering the fact that growth factors play crucial roles in regulating cellular processes, such as proliferation, differentiation, and survival, they could have therapeutic potential for hNDDs, provided appropriate dosing and safe delivery approaches are ensured. This article presents a detailed overview of growth factors, and explores their therapeutic potential in treating hNDDs, emphasizing their roles in neuronal survival, growth, and synaptic plasticity. However, challenges such as proper dosing, delivery methods, and patient variability can hinder their clinical application.

Abstract Background Our aim was attempting to find proteins involved in the pain process and correlating with pain but not degree of inflammation in children with juvenile idiopathic arthritis (JIA), using a proteomics panel. Methods A total of 87 plasma samples were collected from 51 children with JIA (51 at diagnosis in a higher disease activity state, 18 at follow-up in a lower disease activity state) and 18 healthy controls. Relative levels of 92 proteins related to a wide range of biological processes in inflammation were obtained using a proximity extension assay panel. Comparisons between children with and without JIA, in different disease categories, by juvenile disease activity score (JADAS27) and degree of pain on a visual analogue scale (VAS), were performed using parametric and non-parametric statistical methods. Results Nineteen proteins involved in arthritic inflammation, such as interleukin 6 (IL-6) and S100 protein A12, were higher in patients with JIA than controls, seven decreased significantly during treatment, and 18 correlated significantly with JADAS27. Three proteins correlated with pain VAS scores in unadjusted analyses: the glial cell line-derived neurotrophic factor (GDNF), transforming growth factor beta, and IL-18R1. Levels of GDNF correlated significantly with pain VAS scores but not with JADAS27. Conclusions Plasma levels of 18 of 92 tested proteins correlated with degree of disease activity. Levels of three proteins correlated with pain, and levels of one, GDNF, originating from neural cells, correlated with pain without correlating with inflammatory degree, suggesting that it may play a role in pain in JIA. Further studies in larger cohorts are warranted.

Abstract RET (REarranged during Transfection) is a receptor tyrosine kinase that transduces various external stimuli into biological functions, such as survival and differentiation, in neurons. In the current study, we developed an optogenetic tool for modulating RET signaling, termed optoRET, combining the cytosolic region of human RET with a blue-light–inducible homo-oligomerizing protein. By varying the duration of photoactivation, we were able to dynamically modulate RET signaling. Activation of optoRET recruited Grb2 (growth factor receptor-bound protein 2) and stimulated AKT and ERK (extracellular signal-regulated kinase) in cultured neurons, evoking robust and efficient ERK activation. By locally activating the distal part of the neuron, we were able to retrogradely transduce the AKT and ERK signal to the soma and trigger formation of filopodia-like F-actin structures at stimulated regions through Cdc42 (cell division control 42) activation. Importantly, we successfully modulated RET signaling in dopaminergic neurons of the substantia nigra in the mouse brain. Collectively, optoRET has the potential to be developed as a future therapeutic intervention, modulating RET downstream signaling with light.

The application of glial cell line-derive neurotrophic factor (GDNF) to cell cultures and animal models has demonstrated positive effects upon dopaminergic neuronal survival and development, function, restoration, and protection. On this basis, recombinant GDNF protein has been trialled in the treatment of late-stage human Parkinson's disease patients with only limited success that is likely due to a lack of viable receptor targets in an advanced state of neurodegeneration. The latest research points to more refined approaches of modulating GDNF signalling and an optimal quantity and spatial regulation of GDNF can be extrapolated using regulation of dopamine as a proxy measure. The basic research literature on dopaminergic effects of GDNF in animal models is reviewed, concluding that a twofold increase in natively expressing cells increases dopamine turnover and maximises neuroprotective and beneficial motor effects whilst minimising hyperdopaminergia and other side-effects. Methodological considerations for measurement of dopamine levels and neuroanatomical distinctions are made between populations of dopamine neurons and their respective effects upon movement and behaviour that will inform future research into this still-relevant growth factor. [ABSTRACT FROM AUTHOR]

One cause of human male infertility is a scarcity of spermatogonial stem cells (SSCs) in testes with Sertoli cells that neither produce adequate amounts of GDNF nor form the Sertoli-Sertoli junctions that form the blood-testis barrier (BTB). These patients raise the issue of whether a pool of SSCs, depleted due to inadequate GDNF stimulation, will expand if normal signaling is restored. Here, we reduce adult mouse SSC numbers by 90% using a chemical-genetic approach that reversibly inhibits GDNF signaling. Signal resumption causes all remaining SSCs to replicate immediately, but they primarily form differentiating progenitor spermatogonia. Subsequently, self-renewing replication restores SSC numbers. Testicular GDNF levels are not increased during restoration. However, SSC replication decreases as numbers of SSCs and progenitors increase, suggesting important regulatory interactions among these cells. Finally, sequential loss of SSCs and then pachytene spermatocytes causes dissolution of the BTB, thereby recapitulating another important characteristic of some infertile men.

Glial cell line-derived neurotrophic factor (GDNF) is among the strongest dopamine neuron function- and survival-promoting factors known. Due to this reason, it has clinical relevance in dopamine disorders such as Parkinson’s disease and schizophrenia. In the striatum, GDNF is exclusively expressed in interneurons, which make up only about 0.6% of striatal cells. Despite clinical significance, histological analysis of striatal GDNF system arborization and relevance to incoming dopamine axons, which bear its receptor RET, has remained enigmatic. This is mainly due to the lack of antibodies able to visualize GDNF- and RET-positive cellular processes; here, we overcome this problem by using knock-in marker alleles. We find that GDNF neurons chemoattract RET+ axons at least seven times farther in distance than medium spiny neurons (MSNs), which make up 95% of striatal neurons. Furthermore, we provide evidence that tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is enriched towards GDNF neurons in the dopamine axons. Finally, we find that GDNF neuron arborizations occupy approximately only twelve times less striatal volume than 135 times more abundant MSNs. Collectively, our results improve our understanding of how endogenous GDNF affects striatal dopamine system function.

Background: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new parameters, such as immunological and biochemical factors. Methods: This study was designed as an open-label, one-arm cohort retrospective study to evaluate potential diagnostic biomarkers of repeated infusions of autologous-bone marrow-derived mesenchymal stem cells (BM-MSCs) in 15 confirmed patients with ALS, administered at a dose of 1 × 106 cells/kg BW with a one-month interval, in equal amounts in both an intravenous (IV) and intrathecal (IT) capacity simultaneously, via various biochemical (iron (Fe), ferritin, total-iron-binding capacity (TIBC), transferrin, and creatine kinase (CK)) and immunological parameters (tumor necrosis factor-alpha (TNF-α), neurofilament light chain (NFL), and glial-cell-derived neurotrophic factor (GDNF) levels, evaluated during the three-month follow-up period in serum and cerebrospinal fluid (CSF). Results: Our study indicated that, in the case of immunological biomarkers, TNF-α levels in the CSF showed a significant decrease at month three after transplantation compared with levels at month zero, and the p-value was p < 0.01. No statistically significant changes were observed for other immunological as well as biochemical parameters and a p-value of p > 0.05. Conclusions: These results can indicate the potential benefit of stem cell transfusion in patients with ALS and suggest some diagnostic biomarkers. Several studies are required to approve these results.

Despite its established neuroprotective effect on dopaminergic neurons and encouraging phase I results, intraputaminal GDNF administration failed to demonstrate significant clinical benefits in Parkinson’s disease patients. Different human GDNF doses were delivered in the striatum of rats with a progressive 6-hydroxydopamine lesion using a sensitive doxycycline-regulated AAV vector. GDNF treatment was applied either continuously or intermittently (2 weeks on/2 weeks off) during 17 weeks. Stable reduction of motor impairments as well as increased number of dopaminergic neurons and striatal innervation were obtained with a GDNF dose equivalent to 3- and 10-fold the rat endogenous level. In contrast, a 20-fold increased GDNF level only temporarily provided motor benefits and neurons were not spared. Strikingly, oxidized DNA in the substantia nigra increased by 50% with 20-fold, but not 3-fold GDNF treatment. In addition, only low-dose GDNF allowed to preserve dopaminergic neuron cell size. Finally, aberrant dopaminergic fiber sprouting was observed with 20-fold GDNF but not at lower doses. Intermittent 20-fold GDNF treatment allowed to avoid toxicity and spare dopaminergic neurons but did not restore their cell size. Our data suggest that maintaining GDNF concentration under a threshold generating oxidative stress is a pre-requisite to obtain significant symptomatic relief and neuroprotection.

The discovery of the neurotrophins and their potent survival and trophic effects led to great enthusiasm about their therapeutic potential to rescue dying neurons in neurodegenerative diseases. The further discovery that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and glial cell linederived neurotrophic factor (GDNF) had potent survival-promoting activity on motor neurons led to the proposal for their use in motor neuron diseases such as amyotrophic lateral sclerosis (ALS). In this review we synthesize the literature pertaining to the role of NGF, BDNF, CNTF and GDNF on the development and physiology of spinal motor neurons, as well as the preclinical studies that evaluated their potential for the treatment of ALS. Results from the clinical trials of these molecules will also be described and, with the aid of decades of hindsight, we will discuss what can reasonably be concluded and how this information can inform future clinical development of neurotrophic factors for ALS. [ABSTRACT FROM AUTHOR]

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists. [ABSTRACT FROM AUTHOR]

Objective: The nucleus ambiguus (NAmb) is a column of neurons in the medulla oblongata, involved in bulbar functions. Expression of Glial Cell‐Derived Neurotrophic Factor (GDNF) and its receptors (GDNFR) is observed within the cell bodies during reinnervation following recurrent laryngeal nerve (RLN) injury. Little is known regarding GDNFR expression in the formation of the NAmb and the laryngeal innervation during embryogenesis. Understanding the timing and pattern of GDNFR expression in embryogenesis versus after RLN injury may provide insights into therapeutic targets for regeneration after RLN injury. Study Design: Laboratory experiment. Methods: Rat brainstems at E14.5/E16.5/E18.5/E20.5/adult were stained for GDNFR: GFRα‐1/GFRα‐2/GFRα‐3/Ret. Islet1 and choline acetyltransferase were used as cell body markers. Sections were observed using fluorescent microscopy and quantified through manual cell counting. Results: Expression of GFRα‐1, GFRα‐3, and Ret was identified within the NAmb, hypoglossal, and facial nuclei of the adult medulla. During development, GFRα‐1 immunoreactivity was seen at E20.5. GFRα‐2 expression was not observed at any timepoint. GFRα‐3 expression began at E16.5. Ret expression within nerve fibers in the NAmb were observed beginning at E14.5, but never in the cell bodies. Conclusion: Embryonic GDNFR expression in the NAmb differs from that of the adult after RLN injury. The developing brainstem experienced upregulation at discrete timepoints with signaling sustained through adulthood. In contrast, adult RLN‐transected rats experienced patterns of up and down regulation. GFRα‐1 may contribute to muscle targeting and neuromuscular junction maturation, GFRα‐3 may contribute to both, as well as axon guidance. It is likely that GDNF is functioning via a Ret‐independent pathway. Level of Evidence: NA Laryngoscope, 133:2240–2247, 2023 [ABSTRACT FROM AUTHOR]

Objective: To explore the influence of protein arginine methyltransferase 8 (PRMT8) regulating glial cell‐derived neurotrophic factor (GDNF) on neuron ferroptosis and macrophage polarization in spinal cord injury (SCI). Methods: A rat model of SCI was established through an injury induced by an external force. Basso, Beattie, and Bresnahan score, hematoxylin and eosin staining, and immunofluorescence were used, respectively, to detect changes in rat locomotion, spinal cord histopathology, and NeuN expression in the spinal cord. Iron content in the spinal cord and levels of malondialdehyde and glutathione were measured using detection kits. Transmission electron microscopy was used to reveal the morphological characteristics of mitochondria. Western blotting was performed to detect PRMT8, GDNF, cystine/glutamate transporter XCT, glutathione peroxidase 4, 4‐hydroxynonenal, heme oxygenase‐1, inducible nitric oxide synthase (iNOS), CD16, and arginase 1 (Arg1). The expression levels of iNOS and Arg1 in the spinal cord were visualized by immunofluorescence. ELISA was performed to measure the expression levels of IL‐6, IL‐1β, and TNF‐α. Rat dorsal root ganglion (DRG) neurons and RMa‐bm rat macrophages were treated with lipopolysaccharide under hypoxic conditions. The viability and iron content of the neurons were detected using Cell Counting Kit‐8 and a specific probe, respectively. Flow cytometry and immunofluorescence were used to assess macrophage polarization. Chromatin immunoprecipitation was used to identify the binding of PRMT8 to the GDFN promoter. Results: Neuronal ferroptosis and M1 macrophage polarization were promoted, and PRMT8 expression was downregulated in SCI. PRMT8 overexpression exerted therapeutic effects on injured DRG neurons and RMa‐bm cells. Moreover, PRMT8 overexpression inhibited ferroptosis and M1 macrophage polarization in rats with SCI. PRMT8 promoted GDNF expression by catalyzing H3K4 methylation. Knockdown of GDNF counteracted the therapeutic effects of PRMT8 overexpression. Conclusion: Overexpression of PRMT8 may inhibit ferroptosis and M1 macrophage polarization by increasing GDNF expression, thereby alleviating SCI. [ABSTRACT FROM AUTHOR]

To investigate the roles of calcineurin (CN) in glial cells, we previously generated conditional knockout (CKO) mice lacking CNB1 in glial cells. Because these CKO mice showed dysfunction and inflammation of the small intestine in addition to growth impairment and postweaning death, we have focused on enteric glial cells (EGCs) in the small intestine. In this study, we examined the effects of CNB1 deficiency on the proliferation and survival of EGCs and the expression and secretion of EGC-derived substances in culture to reveal the mechanisms of how CNB1 deficiency leads to dysfunction and inflammation of the small intestine. In primary myenteric cultures of the small intestine, EGCs from the CKO mice showed reduced proliferation and increased apoptosis compared with EGCs from control mice. In purified EGC cultures from the CKO mice, Western blot analysis showed increased expression of S100B, iNOS, GFAP, and GDNF, and increased phosphorylation of NF-κB p65. In the supernatants of purified EGC cultures from the CKO mice, ELISA showed reduced secretion of TGF-β1. In contrast, GDNF secretion was not altered in purified EGC cultures from the CKO mice. Furthermore, treatment with an S100B inhibitor partially rescued the CKO mice from growth impairment and postweaning death in vivo. In conclusion, CNB1 deficiency leads to reduced proliferation and increased apoptosis of EGCs and abnormal expression and secretion of EGC-derived substances, which may contribute to dysfunction and inflammation of the small intestine. [ABSTRACT FROM AUTHOR]

Background: Our aim was attempting to find proteins involved in the pain process and correlating with pain but not degree of inflammation in children with juvenile idiopathic arthritis (JIA), using a proteomics panel. Methods: A total of 87 plasma samples were collected from 51 children with JIA (51 at diagnosis in a higher disease activity state, 18 at follow-up in a lower disease activity state) and 18 healthy controls. Relative levels of 92 proteins related to a wide range of biological processes in inflammation were obtained using a proximity extension assay panel. Comparisons between children with and without JIA, in different disease categories, by juvenile disease activity score (JADAS27) and degree of pain on a visual analogue scale (VAS), were performed using parametric and non-parametric statistical methods. Results: Nineteen proteins involved in arthritic inflammation, such as interleukin 6 (IL-6) and S100 protein A12, were higher in patients with JIA than controls, seven decreased significantly during treatment, and 18 correlated significantly with JADAS27. Three proteins correlated with pain VAS scores in unadjusted analyses: the glial cell line-derived neurotrophic factor (GDNF), transforming growth factor beta, and IL-18R1. Levels of GDNF correlated significantly with pain VAS scores but not with JADAS27. Conclusions: Plasma levels of 18 of 92 tested proteins correlated with degree of disease activity. Levels of three proteins correlated with pain, and levels of one, GDNF, originating from neural cells, correlated with pain without correlating with inflammatory degree, suggesting that it may play a role in pain in JIA. Further studies in larger cohorts are warranted. [ABSTRACT FROM AUTHOR]

RET (REarranged during Transfection) is a receptor tyrosine kinase that transduces various external stimuli into biological functions, such as survival and differentiation, in neurons. In the current study, we developed an optogenetic tool for modulating RET signaling, termed optoRET, combining the cytosolic region of human RET with a blue-light–inducible homo-oligomerizing protein. By varying the duration of photoactivation, we were able to dynamically modulate RET signaling. Activation of optoRET recruited Grb2 (growth factor receptor-bound protein 2) and stimulated AKT and ERK (extracellular signal-regulated kinase) in cultured neurons, evoking robust and efficient ERK activation. By locally activating the distal part of the neuron, we were able to retrogradely transduce the AKT and ERK signal to the soma and trigger formation of filopodia-like F-actin structures at stimulated regions through Cdc42 (cell division control 42) activation. Importantly, we successfully modulated RET signaling in dopaminergic neurons of the substantia nigra in the mouse brain. Collectively, optoRET has the potential to be developed as a future therapeutic intervention, modulating RET downstream signaling with light. [ABSTRACT FROM AUTHOR]

Objective: The neurodevelopmental hypothesis of schizophrenia suggests that alterations of glial fibrillary acidic protein (GFAP) and glial cell line-derived neurotrophic factor (GDNF) functions may play a role in the pathogenesis of schizophrenia. However, there is limited information about the relationship of these molecules with the clinical features of schizophrenia. In this study, it was aimed to compare patients with schizophrenia and healthy controls in terms of serum GFAP and GDNF levels and to investigate the effects of clinical parameters on serum levels of molecules in patients with schizophrenia. Method: 37 patients with schizophrenia followed in the psychosis unit and 37 age- and sex-matched healthy controls without a history of psychiatric disease were recruited in study. The patients evaluated through the Turkish version of positive and negative syndrome scale. On the other hand, sociodemographic question form was applied to both the patients and the healthy controls. Results: Serum GDNF and GFAP levels of patients with schizophrenia were significantly lower than those of healthy controls. Furthermore, serum GDNF levels were negatively correlated with general and negative syndrome scales (PANSS) in these patients. Conclusion: It has been observed that there is a relationship between PANSS and changes in the GDNF levels of schizophrenia patients. However, larger clinical studies in which these markers are also measured in cerebrospinal fluid are needed to understand the biological mechanisms underlying these associations and to understand whether glial markers could be useful as biomarkers for the diagnosis of schizophrenia. [ABSTRACT FROM AUTHOR]