Pathogenesis Of Parkinson's Disease Research Articles

CSF GPNMB in Parkinson's disease: A potential association with age and microglial activation

Background Recent evidence suggests a link between glycoprotein non-metastatic melanoma protein B (GPNMB) and Parkinson's disease (PD) pathogenesis. Although elevated plasma GPNMB levels associated with disease severity have been reported in PD, cerebrospinal fluid (CSF) alterations remain elusive. Objective To explore CSF GPNMB alterations and its clinical significance in PD. Methods This study enrolled 118 sporadic PD patients and 40 controls. We examined the potential associations between CSF GPNMB levels and the clinical characteristics or biomarkers of neurodegenerative pathogenesis. Results PD patients had higher CSF GPNMB levels than controls ( p = 0.0159). In the PD group, CSF GPNMB levels correlated with age (age at examination: rs = 0.2511, p = 0.0061; age at onset: rs = 0.2800, p = 0.0021) and the severity of motor and cognitive dysfunction (MDS-UPDRS III score: rs = 0.1998, p = 0.0347; Mini-Mental State Examination score: rs = −0.1922, p = 0.0370). After correcting for multiple comparisons, the correlation with age at onset remained significant. CSF GPNMB levels were also positively correlated with CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in both the PD ( rs = 0.3582, p < 0.0001) and control ( rs = 0.4743, p = 0.0023) groups. Furthermore, multiple regression analysis revealed CSF sTREM2 level as the strongest determinant of CSF GPNMB levels in the PD group (t-value = 3.49, p = 0.0007). Conclusions Elevated CSF GPNMB levels, linked with age and microglial activation, may be a valuable marker for understanding the interplay between aging, neuroinflammation, and PD pathology.

Molecular basis of the development of Parkinson's disease.

Parkinson's disease is one of the most prevalent neurodegenerative motor disorders worldwide with postural instability, bradykinesia, resting tremor and rigidity being the most common symptoms of the disease. Despite the fact that the molecular mechanisms of Parkinson's disease pathogenesis have already been well described, there is still no coherent picture of the etiopathogenesis of this disease. According to modern concepts, neurodegeneration is induced mainly by oxidative stress, neuroinflammation, dysregulation of cerebral proteostasis, apoptotic dysregulation, and impaired autophagy. This review describes how various factors contribute to neurodegeneration in Parkinson's disease. Understanding the factors affecting fundamental cellular processes and responsible for disease progression may help develop therapeutic strategies to improve the quality of life of patients suffering from the disease. The review also discusses the role of calpains in the development of Parkinson's disease. It is known that α-synuclein is a substrate of calcium-dependent proteases of the calpain family. Truncated forms of α-synuclein are not only involved in the process of formation of the aggregates, but also increase their toxicity.

Glutathione S-transferase: A keystone in Parkinson's disease pathogenesis and therapy.

Parkinson's disease is a progressive neurodegenerative disorder that predominantly affects motor function due to the loss of dopaminergic neurons in the substantia nigra. It presents significant challenges, impacting millions worldwide with symptoms such as tremors, rigidity, bradykinesia, and postural instability, leading to decreased quality of life and increased morbidity. The pathogenesis of Parkinson's disease is multifaceted, involving complex interactions between genetic susceptibility, environmental factors, and aging, with oxidative stress playing a central role in neuronal degeneration. Glutathione S-Transferase enzymes are critical in the cellular defense mechanism against oxidative stress, catalysing the conjugation of the antioxidant glutathione to various toxic compounds, thereby facilitating their detoxification. Recent research underscores the importance of Glutathione S-Transferase in the pathophysiology of Parkinson's disease, revealing that genetic polymorphisms in Glutathione S-Transferase genes influence the risk and progression of the disease. These genetic variations can affect the enzymatic activity of Glutathione S-Transferase, thereby modulating an individual's capacity to detoxify reactive oxygen species and xenobiotics, which are implicated in Parkinson's disease neuropathological processes. Moreover, biochemical studies have elucidated the role of Glutathione S-Transferase in not only maintaining cellular redox balance but also in modulating various cellular signalling pathways, highlighting its neuroprotective potential. From a therapeutic perspective, targeting Glutathione S-Transferase pathways offers promising avenues for the development of novel treatments aimed at enhancing neuroprotection and mitigating disease progression. This review explores the evident and hypothesized roles of Glutathione S-Transferase in Parkinson's disease, providing a comprehensive overview of its importance and potential as a target for therapeutic intervention.

Multi-omics analysis reveals the neuroprotective effect of extract against Parkinson's disease in mouse.

To assess Atractylodis Rhizoma Alba extract (ARE) neuroprotective function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and related genes. Examined mRNA-DNA methylation changes induced by ARE in MPTP-induced Parkinson's disease (PD) model's substantia nigra. ARE mitigated MPTP-induced motor impairment in rotarod and open field tests and preserved tyrosine hydroxylase-positive neuronal cells in substantia nigra and striatum. Genome RNA-Sequencing and Methyl-Sequencing in substantia nigra of vehicle/ARE-treated MPTP-induced PD mice showed 84 differentially expressed genes (DEGs) and 1804 differentially methylated regions (DMRs). Upregulated genes involved zinc ion homeostasis, cilium protein localization, and transcription; downregulated genes linked to ephrin receptor signaling, somitogenesis, and gene expression regulation. Hyper/hypomethylated DMRs post-ARE treatment associated with Wnt signaling, mitochondrial organization, dopamine biosynthesis, and hindbrain development. No significant correlation between DEGs and methylated genes related to PD pathogenesis. This research has identified the epigenetic targets of ARE's therapeutic action and gives insight on how ARE protects neurons in Parkinson's disease.

The ultrastructural and proteomic analysis of mitochondria-associated endoplasmic reticulum membrane in the midbrain of a Parkinson's disease mouse model.

Recent studies indicated that the dysregulation of mitochondria-associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. In MPTP-treated mice, transmission electron microscopy was applied for MAM ultrastructural visualization. Nano ultra-high performance liquid chromatography-tandem mass spectrum and bioinformatic analysis were adopted to obtain underlying molecular data of MAM fractions. The loosened, shortened and reduced MAM tethering was found in substantia nigral neurons from MPTP-treated mice. In midbrain MAM proteomics, 158 differentially expressed proteins (DEPs) were identified between two groups. Specific DEPs were validated by western blot and exhibited significantly statistical changes, aligning with proteomic results. Bioinformatic analysis indicated that membrane, cytoplasm and cell projection were three major localizations for DEPs. Biological processes including metabolism, lipid transport, and immunological and apoptotic signaling pathways were greatly affected. For consensus MAM proteins, the enriched pathway analysis revealed the potential relationship between neurodegenerative diseases and MAM. Several biological processes such as peroxisome function and clathrin-mediated endocytosis, were clustered, which provided additional insights into the fundamental molecular pathways associated with MAM. In our study, we demonstrated disrupted ER-mitochondria contacts in an MPTP-induced PD mouse model. The underlying signatures of MAM were revealed by proteomics and bioinformatic analysis, providing valuable insights into its potential role in PD pathogenesis.

Ferroptosis in the Substantia Nigra Pars Compacta of Mice: Triggering Role of Ultrafine Diesel Exhaust Particles and Mitigation by α-Lipoic Acid.

Recent epidemiological and experimental studies have increasingly highlighted the association between environmental pollution, especially ultrafine particulate matter (PM), and the risk of neurodegenerative diseases, such as Parkinson's disease (PD). These previous studies suggest a potential mechanism by which ultrafine PM contributes to neuronal damage through processes, such as iron accumulation and oxidative stress. In this study, we aimed to elucidate the effects of ultrafine PM on ferroptosis, an iron-dependent form of cell death, in the mouse substantia nigra pars compacta (SNc) and to evaluate the protective role of α-lipoic acid (ALA). Mice were exposed to ultrafine diesel exhaust particles (ufDEP), a type of ultrafine PM, intranasally and injected ALA intraperitoneally for seven consecutive days. Iron accumulation and lipid peroxidation were significantly increased, and antioxidant capacity was significantly decreased in the SNc after ufDEP exposure, highlighting the deleterious effects of ufDEP on tyrosine hydroxylase (TH)-positive neurons. In contrast, ALA treatment effectively mitigated these effects by reducing iron accumulation, decreasing lipid peroxidation, and restoring antioxidant levels, resulting in the protection of TH-positive neurons from ferroptotic damage. Our results provide evidence that ufDEP can induce ferroptosis in dopaminergic neurons in the SNc, potentially contributing to PD pathogenesis. Furthermore, ALA showed protective effects against ufDEP-induced ferroptotic damage, suggesting its potential as a therapeutic intervention for PD.

The Effect of glna Loss on the Physiological and Pathological Phenotype of Parkinson's Disease C. elegans.

Parkinson's disease (PD) is a common neurodegenerative disease. Glutamate(Glu) excitotoxicity is one of the main pathogenesis of PD. Glutaminase (Gls) is an enzyme primarily responsible for catalyzing the hydrolysis and deamidation of glutamine (Gln) to produce Glu and ammonia. Inhibiting the function of Gls may have a beneficial effect on the treatment of PD by reducing the production of Glu. The homologous gene of Gls in C. elegans is glna. To explore the effects of glna loss on physiological and pathological phenotype of PD C. elegans, and to provide new ideas and references for the research and treatment of PD. We used PD C. elegans UA44 and QIN27 to detect development and lifespan, behavior, degeneration of dopaminergic neurons, lipid levels, ROS levels, expression levels of common amino acids. Glna loss had no significant impact on the development and lifespan of PD C. elegans. Glna loss saved part of the decline of motor function, including the head thrash frequency and the body bend frequency, and the difference was significant. There was a trend of improvement in some motor behaviors, such as the ethanol avoidance experiment, while no improvement was observed in other experiments. Glna loss slowed down the degeneration of dopaminergic neurons. Glna loss increased the lipid levels and ROS levels in C. elegans. Glna loss decreased Glu content and increased Gln content in C. elegans. The effect of glna loss on PD C. elegans may be the result of multiple factors, such as the tissue types of α-syn expression in C. elegans, the PD C. elegans model used, the adverse effects of glna loss on other systems, and the changes in ROS levels in C. elegans. The specific mechanisms causing these phenomena are still unclear and need to be further explored. Glna loss has a certain protective effect on dopaminergic neurons in PD C. elegans, while the improvement effect on movement and behavior is limited.

The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons

BackgroundVariants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified.MethodsHere, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils.ResultsWe find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein.ConclusionsThese results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

A multi-region single nucleus transcriptomic atlas of Parkinson’s disease

Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder, characterized by motor and cognitive impairments, that affects >1% of the population over the age of 60. The pathogenesis of PD is complex and remains largely unknown. Due to the cellular heterogeneity of the human brain and changes in cell type composition with disease progression, this complexity cannot be fully captured with bulk tissue studies. To address this, we generated single-nucleus RNA sequencing and whole-genome sequencing data from 100 postmortem cases and controls, carefully selected to represent the entire spectrum of PD neuropathological severity and diverse clinical symptoms. The single nucleus data were generated from five brain regions, capturing the subcortical and cortical spread of PD pathology. Rigorous preprocessing and quality control were applied to ensure data reliability. Committed to collaborative research and open science, this dataset is available on the AMP PD Knowledge Platform, offering researchers a valuable tool to explore the molecular bases of PD and accelerate advances in understanding and treating the disease.

White matter lesions contribute to motor and non-motor disorders in Parkinson's disease: a critical review.

Parkinson's disease (PD) is a prevalent neurodegenerative disease, characterized by movement disorders and non-motor symptoms like cognitive impairment and depression. Degeneration of dopaminergic neurons in the substantia nigra and Lewy bodies have long been considered as main neuropathological changes. However, recent magnetic resonance imaging (MRI) studies have shown that white matter lesions (WMLs) were present in PD patients. WMLs are characterized by loss or impairment of myelin sheath in central nerve fibers, which are closely correlated with motor and cognitive dysfunction in PD. WMLs alterations precede nigrostriatal neuronal losses and can independently affect the clinical severity or characteristics of motor coordination in PD patients. Currently, the exact mechanism of WMLs involvement in the occurrence and development of PD remains unclear. It is speculated that WMLs may participate in the pathogenesis of PD by disrupting important connections in brain or promoting axonal degeneration. In this review, we will discuss the pathological changes and mechanisms of WMLs, elaborate the impact of WMLs on the progression of PD, clarify the importance of WMLs in PD pathogenesis, and thus provide novel targets for PD treatments.

Identification of biomarkers in Parkinson's disease by comparative transcriptome analysis and WGCNA highlights the role of oligodendrocyte precursor cells.

Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by the death of dopamine neurons in the substantia nigra. A large number of studies have focused on dopamine neurons themselves, but so far, the pathogenesis of PD has not been fully elucidated. Here, we explored the significance of oligodendrocyte precursor cells (OPCs)/oligodendrocytes in the pathogenesis of PD using a bioinformatic approach. WGCNA analysis suggested that abnormal development of oligodendrocytes may play a key role in early PD. To verify the transcriptional dynamics of OPCs/oligodendrocytes, we performed differential analysis, cell trajectory construction, cell communication analysis and hdWGCNA analysis using single-cell data from PD patients. Interestingly, the results indicated that there was overlap between hub genes and differentially expressed genes (DEGs) in OPCs not in oligodendrocytes, suggesting that OPCs may be more sensitive to PD drivers. Then, we used ROC binary analysis model to identify five potential biomarkers, including AGPAT4, DNM3, PPP1R12B, PPP2R2B, and LINC00486. In conclusion, our work highlights the potential role of OPCs in driving PD.

Exploring α-synuclein Interaction Partners and their Potential Clinical Implications for Parkinson's Disease.

Alpha-synuclein aggregates are strongly associated with Parkinson's disease (PD), a degenerative neurological disorder characterized by a progressive loss in motor functions. Our study aimed to unravel the potential interaction partners of α-synuclein for exploring the synucleinpathy of PD related to α-synuclein aggregates. α-synuclein was expressed in E.coli and purified by affinity chromatography followed by isolation and identification of its interaction partners using pulldown assay coupled with LC-MS/MS. The impacts of the identified interaction partners on PD were evaluated based on GSE205450 dataset. Consequently, 157 proteins were identified by the criteria of unique peptide = 5. Four proteins including ACO2, ANT1, ATP5F1B and CKB were confirmed using immunostaining coupled with α-synuclein-pulldown assay. Transcriptomics assay showed that the dominant biological processes influenced by α-synuclein interaction partners with differential expression were energy metabolism. Together with GSE205450, Western blot assay showed that α-synuclein interaction partners involved in energy metabolism were down-regulated in PD patients and the MPTP-lesioned mice. ROC curves indicated their clinical implications as diagnostic indices of PD. Using ANT1 as an example, we found that protein aggregates formed by ANT1 and α-synuclein predominantly solely appeared in the cells and mice with PD-like variations. Thereby, low levels of the interaction partners of α-synuclein associated with energy metabolism were associated with PD pathogenesis via forming protein aggregates. This study provides an insight into developing innovative targets on PD based on synucleinpathy.

Mutated LRRK2 induces a reactive phenotype and alters migration in human iPSC-derived pericyte-like cells

BackgroundPericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson’s disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD.MethodsOur study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality.ResultsWe have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli.ConclusionsIn summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD.

The utilization of CRISPR-Cas9 with human pluripotent stem cell for Parkinson's disease modeling

Abstract. Parkinson's disease (PD), also often referred to as "parkinsonism," is a neurodegenerative disorder. Those afflicted with this condition are frequently elderly, which results in a considerable decline in their quality of life and overall well-being. Although there are major breakthroughs in PD research, there remains an incomplete grasp of the disease's pathogenesis and the formulation of innovative treatment approaches. This has led to an urgent need for a technology that can recapitulate all the features of human PD. The emergence of induced pluripotent stem cells (iPSC) coupled with the rising appeal of Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9 (CRISPR-Cas9) technology, the construction of PD models through the combination of iPSC and CRISPR-Cas9 has emerged as a crucial area of research in the field of PD. Employing patients' somatic cells, transformed into iPSC and integrated with CRISPR-Cas9 for genetic modification, has facilitated the duplication of the genetic makeup of neural cells associated with PD, thereby facilitating the investigation of the influence of diverse genotypes on disease progression and treatment response. This review outlines the application and future development of iPSC and CRISPR-Cas9 technologies for the study of Parkinson's disease pathogenesis. The technology enables scientists to gain a deeper understanding of PD and paves the way for the development of novel therapeutic approaches in the future.

The association between age-related macular degeneration and risk of Parkinson disease: A systematic review and meta-analysis.

Numerous cohort studies have explored the association between age-related macular degeneration (AMD) and Parkinson disease (PD). However, a comprehensive meta-analysis on this topic is currently lacking. This study aims to address this gap by conducting a meta-analysis of existing cohort studies to investigate the relationship between AMD and the risk of developing PD. Relevant studies were systematically identified through thorough searches of the PubMed, Web of Science, Embase, and Cochrane Library databases. Two investigators independently conducted data extraction. Cohort studies meeting the eligibility criteria and providing risk and precision estimates regarding AMD and the risk of PD were included. Pooled hazard ratio (HR) accompanied by 95% confidence interval (CI) were calculated using either a random-effects model or a fixed-effects model. Sensitivity analyses, involving the exclusion of 1 study at a time, were performed to assess the robustness of the findings. Publication bias was evaluated using Egger test. Five studies were included, encompassing a total of 4,771,416 individuals. Among these, 128,771 individuals had AMD, while 4,642,645 individuals did not. The pooled analysis revealed a significant increase in the risk of developing PD for individuals with age-related macular degeneration (hazard ratio [HR] = 1.44; 95% confidence interval [CI]: 1.22-1.71; I2 = 47.3%). Sensitivity analysis confirmed the robustness of the results. For the exploration of the relationship between nAMD and the risk of developing PD, 2 cohorts were included. The pooled analysis demonstrated a significantly elevated risk of PD for individuals with nAMD (HR = 2.21; 95% CI: 1.55-3.16; I2 = 0%). This meta-analysis suggests a significant association between AMD and an increased risk of PD. These findings offer fresh perspectives on PD's etiology and pathogenesis, but should be interpreted with caution given the limitations in establishing causality.

Phytochemicals in Parkinson's Disease: a Pathway to Neuroprotection and Personalized Medicine.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the progressive loss of dopaminergic neurons in the substantia nigra. While current treatments primarily manage symptoms, there is increasing interest in alternative approaches, particularly the use of phytochemicals from medicinal plants. These natural compounds have demonstrated promising neuroprotective potential in preclinical studies by targeting key pathological mechanisms such as oxidative stress, neuroinflammation, and protein aggregation. However, the clinical translation of these phytochemicals is limited due to a lack of robust clinical trials evaluating their safety, efficacy, and pharmacokinetics. This review provides a comprehensive overview of the neuroprotective potential of phytochemicals in PD management, examining the mechanisms underlying PD pathogenesis and emphasizing neuroprotection. It explores the historical and current research on medicinal plants like Mucuna pruriens, Curcuma longa, and Ginkgo biloba, and discusses the challenges in clinical translation, including ethical and practical considerations and the integration with conventional therapies. It further underscores the need for future research to elucidate mechanisms of action, optimize drug delivery, and conduct rigorous clinical trials to establish the safety and efficacy of phytochemicals, aiming to shape future neuroprotective strategies and develop more effective, personalized treatments for PD.

Parkinson's Disease and the Microbiota-Gut-Brain Axis: Metabolites, Mechanisms, and Innovative Therapeutic Strategies Targeting the Gut Microbiota.

The human gut microbiota is diverse and abundant and plays important roles in regulating health by participating in metabolism and controlling physiological activities. The gut microbiota and its metabolites have been shown to affect the functioning of the gut and central nervous system through the microbiota-gut-brain axis. It is well established that microbiota play significant roles in the pathogenesis and progression of Parkinson's disease (PD). Disorders of the intestinal microbiota and altered metabolite levels are closely associated with PD. Here, the changes in intestinal microbiota and effects of metabolites in patients with PD are reviewed. Potential mechanisms underlying intestinal microbiota disorders in the pathogenesis of PD are briefly discussed. Additionally, we outline the current strategies for the treatment of PD that target the gut microbiota, emphasizing the development of promising novel strategies.

Genetically modified E. Coli secreting melanin (E.melanin) activates the astrocytic PSAP-GPR37L1 pathway and mitigates the pathogenesis of Parkinson’s disease

The characteristic neuropathology of Parkinson’s disease (PD) involves the abnormal accumulation of phosphorylated α-synuclein (αSyn), as well as a significant decrease in neuromelanin (NM) levels within dopamine neurons (DaNs). Unlike αSyn aggregates, the relationship between NM levels and PD pathogenesis is not well understood. In this study, we engineered an E. coli MG1655 strain to produce exosomes containing melanin (E.melanin), and investigated its potential neuroprotective effects on DaNs in the context of PD. By employing a combination of cell cultures, biochemical studies, single nuclear RNA sequencing (snRNA seq), and various in vivo validations, we found that administration of E.melanin effectively alleviated DaNs loss and improved motor behavior impairments observed in both pharmacological and transgenic PD mouse models. Mechanistically, snRNA seq data suggested that E.melanin activated the PSAP-GPR37L1 signaling pathway specifically within astrocytes, leading to a reduction in astrocytic engulfment of synapses. Notably, activation of the GPR37L1 receptor using Tx14(A) peptide successfully rescued motor defects as well as protected against DaNs degeneration in mice with PD. Overall, our findings provide novel insights into understanding the molecular mechanisms underlying melanin’s protective effects on DaNs in PD while offering potential strategies for manipulating and treating its pathophysiological progression.

Intersection of Sleep Disorders and Parkinson Disease: Unveiling the Bidirectional Relationship.

Patients with Parkinson's Disease (PD) frequently exhibit non-motor symptoms, particularly sleep disturbances. Sleep disorders in PD patients are intricately linked to the pathogenesis and progression of PD itself, exacerbating neurodegenerative processes and worsening patient quality of life. This review underscores the significance of sleep disorders in PD, highlighting their prevalence, impact on disease progression, and the bidirectional relationship between sleep disruption and neurodegeneration. It aims to enhance clinician awareness for better diagnosis and management of sleep-related comorbidities in PD. A comprehensive literature search was conducted in PubMed and Scopus using key terms such as "sleep disorders", "Parkinson's disease", "REM sleep behavior disorder", "restless legs syndrome", "insomnia", "obstructive sleep apnea", "excessive daytime sleepiness", "circadian rhythm disorders", "sleep and neurodegeneration". Sleep disorders are prevalent in PD affecting up to 90% of patients. Conditions such as insomnia, REM sleep behavior disorder, restless legs syndrome, obstructive sleep apnea, excessive daytime sleepiness, and circadian rhythm disorders are commonly reported. These disorders are linked to multifactorial biological mechanisms and are associated with more severe disease phenotypes. Of note, several evidence shows that sleep abnormalities may contribute to neuroinflammation and neurodegeneration, further accelerating the disease course. Sleep disturbances are critical non-motor symptoms in PD. Early diagnosis and tailored management of sleep disorders are essential for improving clinical outcomes and potentially offering neuroprotective benefits.

Gut Microbiome and Its Role in Parkinson's Disease.

Parkinson's disease (PD) afflicted more than 8.5 million people globally in 2019, as the prevalence of the condition more than doubled during the preceding 25 years. Both non-motor symptoms, such as mood disorders and cognitive impairment, and motor symptoms, such as tremors and rigidity, are indicative of this progressive neurodegenerative disease. Recent data indicates a significant role for the gut microbiome in PD pathogenesis and progression, emphasizing the microbiota-gut-brain axis. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, this systematic review summarizes our current knowledge about the function of the gut microbiome in PD, highlighting recurrent microbial alterations and assessing microbiome-based treatment strategies. The review revealed several consistent patterns in the gut microbiota of PD patients, including reduced microbial diversity and specific taxonomic alterations, including a drop in Firmicutes abundance and an increase in Proteobacteria abundance. Functional changes in the gut microbiome, such as altered short-chain fatty acid (SCFA) production and tryptophan metabolism, were also noted. These microbial changes were observed even in early-stage and drug-naïve PD patients, suggesting they are not merely a consequence of disease progression or medication use. The review highlighted potential mechanisms linking gut microbiome alterations to PD, including increased intestinal permeability, neuroinflammation, and modulation of alpha-synuclein aggregation. Probiotics, prebiotics, and fecal microbiota transplantation are a few interventions that try to modify the gut microbiome and might be possible to halt the advancement of PD and enhance patients' quality of life with the condition. Future research should focus on establishing causality through large-scale longitudinal studies, standardizing microbiome analysis methods, and exploring personalized microbiome-based therapies.