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Introduction: Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood. Objective: The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder. Methods: The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis. Results: It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor. Conclusions: In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor. [ABSTRACT FROM AUTHOR]

Abstract Introduction Bipolar disorder is a psychiatric condition characterized by the coexistence of depression and mania. Diagnosis of this disorder can be challenging due to limited pathologic and experimental tools. Treatment compliance is often poor due to medication side effects. Although cathepsin is known to play a significant role in diseases such as tumors and osteoporosis, its role in psychiatric disorders is not yet fully understood. Objective The aim of this study was to investigate the relationship between cathepsin in the blood circulation and bipolar disorder. Methods The causal relationship between cathepsin and different subtypes of bipolar affective disorder was explored using bidirectional Mendelian randomization analysis and multivariate analysis. Results It was found that cathepsin H level was a protective factor for type II bipolar disorder. No potential causal relationship was found between cathepsin H and type I bipolar disorder, but cathepsin B changes with the development of type I bipolar disorder. A causal relationship was found between cathepsin H and cerebral dopamine neurotrophic factor. Conclusions In conclusion, cathepsin H may be a diagnostic target for bipolar II disorder and may play a guiding role in clinical diagnosis. Cathepsin H may have an effect on BD through cerebral dopamine neurotrophic factor.

Abstract Cerebral dopamine neurotrophic factor (CDNF) and its close structural relative, mesencephalic astrocyte-derived neurotrophic factor (MANF), are proteins with neurotrophic properties. CDNF protects and restores the function of dopamine (DA) neurons in rodent and non-human primate (NHP) toxin models of Parkinson’s disease (PD) and therefore shows promise as a drug candidate for disease-modifying treatment of PD. Moreover, CDNF was found to be safe and to have some therapeutic effects on PD patients in phase 1/2 clinical trials. However, the mechanism underlying the neurotrophic activity of CDNF is unknown. In this study, we delivered human CDNF (hCDNF) to the brain using an adeno-associated viral (AAV) vector and demonstrated the neurotrophic effect of AAV-hCDNF in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. AAV-hCDNF resulted in the expression of hCDNF in the striatum (STR) and substantia nigra (SN), and no toxic effects on the nigrostriatal pathway were observed. Intrastriatal injection of AAV-hCDNF reduced motor impairment and partially alleviated gait dysfunction in the acute MPTP mouse model. In addition, gene therapy with AAV-hCDNF had significant neuroprotective effects on the nigrostriatal pathway and decreased the levels of interleukin 1beta (IL-1β) and complement 3 (C3) in glial cells in the acute MPTP mouse model. Moreover, AAV-hCDNF reduced C/EBP homologous protein (CHOP) and glucose regulatory protein 78 (GRP78) expression in astroglia. These results suggest that the neuroprotective effects of CDNF may be mediated at least in part through the regulation of neuroinflammation and the UPR pathway in a mouse MPTP model of PD in vivo.

Cerebral dopamine neurotrophic factor (CDNF) and its close structural relative, mesencephalic astrocyte-derived neurotrophic factor (MANF), are proteins with neurotrophic properties. CDNF protects and restores the function of dopamine (DA) neurons in rodent and non-human primate (NHP) toxin models of Parkinson's disease (PD) and therefore shows promise as a drug candidate for disease-modifying treatment of PD. Moreover, CDNF was found to be safe and to have some therapeutic effects on PD patients in phase 1/2 clinical trials. However, the mechanism underlying the neurotrophic activity of CDNF is unknown. In this study, we delivered human CDNF (hCDNF) to the brain using an adeno-associated viral (AAV) vector and demonstrated the neurotrophic effect of AAV-hCDNF in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. AAV-hCDNF resulted in the expression of hCDNF in the striatum (STR) and substantia nigra (SN), and no toxic effects on the nigrostriatal pathway were observed. Intrastriatal injection of AAV-hCDNF reduced motor impairment and partially alleviated gait dysfunction in the acute MPTP mouse model. In addition, gene therapy with AAV-hCDNF had significant neuroprotective effects on the nigrostriatal pathway and decreased the levels of interleukin 1beta (IL-1β) and complement 3 (C3) in glial cells in the acute MPTP mouse model. Moreover, AAV-hCDNF reduced C/EBP homologous protein (CHOP) and glucose regulatory protein 78 (GRP78) expression in astroglia. These results suggest that the neuroprotective effects of CDNF may be mediated at least in part through the regulation of neuroinflammation and the UPR pathway in a mouse MPTP model of PD in vivo. [ABSTRACT FROM AUTHOR]

The existent pre‐clinical models of Parkinson's disease do not simultaneously recapitulate severe degeneration of dopamine neurons and the occurrence of alpha‐synuclein (aSyn) aggregation in one study system. In this study, we injected aSyn pre‐formed fibrils (PFF) and 6‐hydroxydopamine (6‐OHDA) unilaterally into the striatum of C57BL/6 wild‐type male mice at an interval of 2 weeks to induce aggregation of aSyn protein and trigger the loss of dopamine neurons simultaneously in one model and studied the behavioural effects of the combination in these mice. 6‐OHDA was tested at three different doses, and 2 μg of 6‐OHDA combined with PFF‐induced aSyn aggregation was found to produce the most optimal disease phenotype. At 14 weeks timepoint, mice injected with a combination of PFF and 6‐OHDA sustained significant damage to the nigrostriatal pathway and exhibited aSyn‐positive aggregation. Our data suggest that the neurons that formed large aSyn aggregates were particularly vulnerable to 6‐OHDA‐induced degeneration. We also demonstrate the manifestation of a relatively aggressive pathology in 2‐ to 4‐month‐old mice, as compared to younger 7‐ to 9‐week‐old ones. Furthermore, cerebral dopamine neurotrophic factor (CDNF) administered intrastriatally rescued dopamine neurons and motor behaviour of the animals to some extent from 6‐OHDA toxicity. However, no such effect could be seen in the novel 6‐OHDA + PFFs combination model. For the first time, we demonstrate the combined effect of PFF and 6‐OHDA simultaneously in one model. We further discuss the scope for further optimizing this combination model to develop it as a promising pre‐clinical platform for drug screening and development. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the serum levels of anti-myelin basic protein (anti-MBP), anti-myelin oligodentrocyte glycoprotein (anti-MOG), myelin-associated glycoprotein (MAG), high-sensitivity C-reactive protein (hs-CRP), cerebral dopamine neurotrophic factor (CDNF), cerebellin-1, and reelin and their relationships with clinical severity and irritability behaviours in children with attention deficit (AD) hyperactivity disorder (ADHD) and typically developing (TD) healthy controls., Methods: In this study, 141 children with ADHD between the ages of 8 and 14 years who were medication-free and 135 TD healthy controls were included. The serum levels of anti-MBP, anti-MOG, MAG, CDNF, hs-CRP, cerebellin, and reelin were measured using enzyme-linked immunosorbent assay kits. The Turgay Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-based Screening and Evaluation Scale for Attention Deficit and Disruptive Behavior Disorders-Parent Form (TDSM-IV-O) and the affective reactivity index (ARI) scale were used to assess clinical severity and irritability behaviours in the children., Results: The MAG, CDNF, hs-CRP, reelin, and cerebellin levels were significantly higher in the ADHD group than in the control group, but no significant differences in anti-MBP and anti-MOG levels were found between the groups. Compared with the controls, the patients with ADHD showed significantly higher scores on the ARI self- and parent-report scales. The reelin, hs-CRP, and MAG levels were significantly associated with the TDSM-IV-O AD scores, AD and oppositional defiant (OD) disorder scores and hyperactivity, and OD and conduct disorder scores, respectively. Hs-CRP was significantly associated with anti-MBP and cerebellin levels. In an analysis of covariance, the results were unchanged even after controlling for potential confounders such as age, body mass index, and sex., Conclusion: This study demonstrates that MAG, CDNF, hs-CRP, reelin, and cerebellin levels may play a potential role in the pathogenesis of ADHD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cerebral reperfusion injury in stroke, stemming from interconnected thrombotic and inflammatory signatures, often involves platelet activation, aggregation and its interaction with various immune cells, contributing to microvascular dysfunction. However, the regulatory mechanisms behind this platelet activation and the resulting inflammation are not well understood, complicating the development of effective stroke therapies. Utilizing animal models and platelets from hemorrhagic stroke patients, our research demonstrates that human cerebral dopamine neurotrophic factor (CDNF) acts as an endogenous antagonist, mitigating platelet aggregation and associated neuroinflammation. CDNF moderates mitochondrial membrane potential, reactive oxygen species production, and intracellular calcium in activated platelets by interfering with GTP binding to Rap1b, thereby reducing Rap1b activation and downregulating the Rap1b-MAPK-PLA2 signaling pathway, which decreases release of the pro-inflammatory mediator thromboxane A2. In addition, CDNF reduces the inflammatory response in BV2 microglial cells co-cultured with activated platelets. Consistent with ex vivo findings, subcutaneous administration of CDNF in a rat model of ischemic stroke significantly reduces platelet activation, aggregation, lipid mediator production, infarct volume, and neurological deficits. In summary, our study highlights CDNF as a promising therapeutic target for mitigating platelet-induced inflammation and enhancing recovery in stroke. Harnessing the CDNF pathway may offer a novel therapeutic strategy for stroke intervention., Competing Interests: Declaration of interests M.S. is one of inventors of the CDNF-related patent (7452969), which is owned by the Herantis Pharma Company (Espoo, Finland)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Impairment in dopaminergic pathways has been implicated in several detrimental neuropsychiatric and neurodegenerative disorders, including schizophrenia and Parkinson's disease. Current approved therapeutic drugs for such conditions treat the symptoms, not the underlying cause, as this requires long-term usage that often causes severe extrapyramidal side effects. A novel allosteric modulator, 3(R)-[(2(S)-pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide (PAOPA), selectively attenuates the dopamine D2 receptor and effectively modulates schizophrenia-like symptoms in preclinical animal models. The pharmacokinetics and toxicological evaluation for this drug also presented its effectiveness in reaching targeted therapeutic regions without showing hematological and metabolic abnormalities in chronic treatment. Recent studies have revealed that cerebral dopamine neurotrophic factor (CDNF), an ER located protein secreted upon ER stress, has long-term neuroprotective and neuro-restorative effects on dopaminergic neurons. Given the therapeutic role of PAOPA and the restorative effect of CDNF in the dopaminergic pathway, this study examined the chronic effect of PAOPA treatment on CDNF protein expression in brain regions implicated in neurological disorders. Immunoblot results revealed a 232% striatal increase in CDNF after 7 days of daily injection. Although the mechanism is not entirely understood, this study provides more insight into the potential signalling pathways affected by PAOPA treatment. As extracellular receptor kinase (ERK1/2) is proposed to upregulate CDNF expression following an unfolded protein response and PAOPA treatment increases ERK1/2 expression, PAOPA may indirectly affect CDNF expression by modulating ERK1/2 expression. The restorative effects of CDNF implicate it in the therapeutic mechanism for the potential antipsychotic drug, PAOPA. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) patients experience progressive neurological and cognitive decline attributed to neurodegeneration. Cerebral dopamine neurotrophic factor (CDNF) has been identified to protect and rescue neurons in various preclinical neurodegeneration models. The expression of this protein occurs in both the central nervous system and peripheral blood. Blood platelets exhibit several biochemical impairments similar to the brain tissues of patients with neurological disorders. This study examines CDNF mRNA expression in human blood platelets in healthy subjects and Alzheimer-probable patients.Methods: Platelets were extracted from whole blood from patients. mRNA was extracted to synthesize cDNA and quantify CDNF gene expression from 21 Alzheimer-probable patients and 73 healthy age-matched control subjects using real-time qPCR. Grouping analysis of the data with regard to sex was conducted.Results: CDNF mRNA expression was significantly decreased in Alzheimer-probable patients relative to the control subjects (P<0.05). Further analysis demonstrated reduced CDNF expression in male Alzheimer-probable patients compared with their age and sex-matched controls (P<0.05). However, no change in female subjects was observed. Interestingly, there is a lower level of CDNF expression in the female control group relative to the control male group (P<0.05).Conclusion: Alzheimer-probable male patients demonstrated significant reductions in CDNF expression, suggesting that CDNF plays a significant role in the pathogenesis of AD. In addition, it may assist in diagnosing male Alzheimer patients. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models. HER-096 is metabolically stable and able to penetrate to cerebrospinal (CSF) and brain interstitial fluids (ISF) after subcutaneous administration, with an extended CSF and brain ISF half-life compared to plasma. Subcutaneously administered HER-096 modulated UPR pathway activity, protected dopamine neurons, and reduced α-synuclein aggregates and neuroinflammation in substantia nigra of aged mice with synucleinopathy. Peptidomimetic HER-096 is a candidate for development of a disease-modifying therapy for Parkinson's disease with a patient-friendly route of administration. [Display omitted] • HER-096 mimics CDNF action by modulating UPR pathway signaling • HER-096 is proteolysis-resistant and can penetrate the blood-brain barrier • HER-096 shows disease modifying potential in an animal model of PD HER-096 is a compound developed based on the active site of the human CDNF protein that potentially can slow down the progression of neurodegeneration. HER-096 is able to penetrate the brain after subcutaneous administration and to protect neurons in animal model of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases. [ABSTRACT FROM AUTHOR]