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Biomolecules May 2024The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is...
The primary nucleation process of α-synuclein (AS) that forms toxic oligomeric species is the early stage of the pathological cause of Parkinson's disease. It is well-known that copper influences this primary nucleation process. While significant efforts have been made to solve the structures of polymorphic AS fibrils, the structures of AS oligomers and the copper-bound AS oligomers at the molecular level and the effect of copper concentrations on the primary nucleation are elusive. Here, we propose and demonstrate new molecular mechanism pathways of primary nucleation of AS that are tuned by distinct copper concentrations and by a specific copper-binding site. We present the polymorphic AS dimers bound to different copper-binding sites at the atomic resolution in high- and low-copper concentrations, using extensive molecular dynamics simulations. Our results show the complexity of the primary nucleation pathways that rely on the copper concentrations and the copper binding site. From a broader perspective, our study proposes a new strategy to control the primary nucleation of other toxic amyloid oligomers in other neurodegenerative diseases.
Topics: alpha-Synuclein; Copper; Binding Sites; Molecular Dynamics Simulation; Humans; Protein Multimerization; Protein Binding; Parkinson Disease
PubMed: 38927031
DOI: 10.3390/biom14060627 -
NPJ Parkinson's Disease Jun 2024The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson's disease (PD). Accurate identification of this phase is...
The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson's disease (PD). Accurate identification of this phase is essential for early interventions. Therefore, we investigated the diagnostic value of these research criteria in the general population. Lifelines is an ongoing cohort study of 167,000 participants from the general population of the Northern Netherlands. 160 participants self-reported to have developed PD during three rounds of follow-up of five years each. Data were available to infer six out of eleven risk markers, and six out of twelve prodromal markers. We retrospectively compared the criteria in the prodromal stage of a group of 160 'converters' with 320 age- and sex-matched controls. The overall incidence rate of PD was 0.20 per 1.000 person-years (95% CI: 0.049-0.36), increasing with age and rates were higher in men. The median probability for prodromal PD in PD-converters was 1.29% (interquartile range: 0.46-2.9), compared to 0.83% (0.39-1.8) for controls (P = 0.014). The MDS set of criteria for prodromal PD had an ROC-AUC of 0.577, and was therefore not sufficient to adequately predict conversion to PD. We were unable to predict conversion to PD in the general population using a selection of the prodromal PD research criteria. Ancillary investigations are required to improve the diagnostic accuracy of the criteria, but most are precluded from large-scale use. Strategies, including olfactory tests or alpha-synuclein seeding amplification assays may improve the detection of prodromal PD in the general population.
PubMed: 38926405
DOI: 10.1038/s41531-024-00739-6 -
The FEBS Journal Jun 2024Especially in higher eukaryotes, the N termini of proteins are subject to enzymatic modifications, with the acetylation of the alpha-amino group of nascent polypeptides... (Review)
Review
Especially in higher eukaryotes, the N termini of proteins are subject to enzymatic modifications, with the acetylation of the alpha-amino group of nascent polypeptides being a prominent one. In recent years, the specificities and substrates of the enzymes responsible for this modification, the Nα-terminal acetyltransferases, have been mapped in several proteomic studies. Aberrant expression of, and mutations in these enzymes were found to be associated with several human diseases, explaining the growing interest in protein Nα-terminal acetylation. With some enzymes, such as the Nα-terminal acetyltransferase A complex having thousands of possible substrates, researchers are now trying to decipher the functional outcome of Nα-terminal protein acetylation. In this review, we zoom in on one possible functional consequence of Nα-terminal protein acetylation; its effect on protein folding. Using selected examples of proteins associated with human diseases such as alpha-synuclein and huntingtin, here, we discuss the sometimes contradictory findings of the effects of Nα-terminal protein acetylation on protein (mis)folding and aggregation.
PubMed: 38923676
DOI: 10.1111/febs.17209 -
Journal of Neurochemistry Jun 2024Parkinson's disease (PD) is the second most common neurodegenerative disorder. The primary pathological features of PD include the presence of α-synuclein aggregates... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder. The primary pathological features of PD include the presence of α-synuclein aggregates and Lewy bodies, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Recently, omega-3 fatty acids (ω-3 PUFAs) have been under investigation as a preventive and/or therapeutic strategy for PD, primarily owing to their antioxidant and anti-inflammatory properties. Therefore, the objective of this study was to conduct a systematic review of the literature, focusing on studies that assessed the effects of ω-3 PUFAs in rodent models mimicking human PD. The search was performed using the terms "Parkinson's disease," "fish oil," "omega 3," "docosahexaenoic acid," and "eicosapentaenoic acid" across databases PUBMED, Web of Science, Science Direct, Scielo, and Google Scholar. Following analysis based on predefined inclusion and exclusion criteria, 39 studies were included. Considering behavioral parameters, pathological markers of the disease, quantification of ω-3 PUFAs in the brain, as well as anti-inflammatory, antioxidant, and anti-apoptotic effects, it can be observed that ω-3 PUFAs exhibit a potential neuroprotective effect in PD. In summary, this systematic review presents significant scientific evidence regarding the effects and mechanisms underlying the neuroprotective properties of ω-3 PUFAs, offering valuable insights for the development of future clinical investigations.
PubMed: 38923542
DOI: 10.1111/jnc.16154 -
Frontiers in Microbiology 2024Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease...
Longitudinal microbiome investigation throughout prion disease course reveals pre- and symptomatic compositional perturbations linked to short-chain fatty acid metabolism and cognitive impairment in mice.
Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease development and progression, including amyloid-beta (Aβ) and alpha (α)-synuclein pathology in neurodegenerative diseases, conveying the importance of the brain-gut-microbiome axis in such conditions. However, little is known about the longitudinal microbiome landscape and its potential clinical implications in other protein misfolding disorders, such as prion disease. We investigated the microbiome architecture throughout prion disease course in mice. Fecal specimens were assessed by 16S ribosomal RNA sequencing. We report a temporal microbiome signature in prion disease and uncovered alterations in Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae, and Muribaculaceae family members in this disease. Moreover, we determined the enrichment of Bilophila, a microorganism connected to cognitive impairment, long before the clinical manifestation of disease symptoms. Based on temporal microbial abundances, several associated metabolic pathways and resulting metabolites, including short-chain fatty acids, were linked to the disease. We propose that neuroinflammatory processes relate to perturbations of the intestinal microbiome and metabolic state by an interorgan brain-gut crosstalk. Furthermore, we describe biomarkers possibly suitable for early disease diagnostics and anti-prion therapy monitoring. While our study is confined to prion disease, our discoveries might be of equivalent relevance in other proteinopathies and central nervous system pathologies.
PubMed: 38919500
DOI: 10.3389/fmicb.2024.1412765 -
Journal of Neurophysiology Jun 2024Alpha-synuclein (α-syn) is a major component of lewy bodies, which is biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacts (SNpc) to...
OBJECTIVE
Alpha-synuclein (α-syn) is a major component of lewy bodies, which is biomarker of Parkinson's disease (PD). It accumulates in substantia nigra pars compacts (SNpc) to form insoluble aggregates and cause neurotoxicity, which is often accompanied by iron deposition.
METHOD
We compared the iron reductase activity between monomeric α-syn (M-α-syn) and oligomeric α-syn (O-α-syn), investigated the effect of α-syn on iron metabolism of BV2 microglia cells as well.
RESULTS
α-syn had ferric reductase activity, and O-α-syn had stronger enzyme activity than M-α-syn. M-α-syn upregulated iron uptake protein, divalent metal transporter1 (DMT1) expression and iron influx, but did not regulate iron release protein, ferroportin1 (FPN1) expression and iron efflux. O-α-syn elevated the expression of both DMT1 and FPN1, thus increased the iron influx and efflux in BV2 microglial cells, but the expressions of iron regulatory protein1 (IRP1) and hypoxia inducible factor2α (HIF-2α) had no significant change. Moreover, both M-α-syn and O-α-syn could increase the mRNA expressions of TNF-α and IL-1β in BV2 microglia cells.
CONCLUSION
Both types of α-syn can activate microglia, which leads to increased expressions of pro-inflammatory factors. α-syn can affect DMT1 and FPN1 expressions in BV2 microglia cells, which might be through its ferric reductase activity.
PubMed: 38919150
DOI: 10.1152/jn.00106.2024 -
Virology Jun 2024Alpha-synuclein (α-syn), known for its pivotal role in Parkinson's disease, has recently emerged as a significant player in neurotropic RNA virus infections.... (Review)
Review
Alpha-synuclein (α-syn), known for its pivotal role in Parkinson's disease, has recently emerged as a significant player in neurotropic RNA virus infections. Upregulation of α-syn in various viral infections has been found to impact neuroprotective functions by regulating neurotransmitter synthesis, vesicle trafficking, and synaptic vesicle recycling. This review focuses on the multifaceted role of α-syn in controlling viral replication by modulating chemoattractant properties towards microglial cells, virus-induced ER stress signaling, anti-oxidative proteins expression. Furthermore, the text underlines the α-syn-mediated regulation of interferon-stimulated genes. The review may help suggest potential therapeutic avenues for mitigating the impact of RNA viruses on the central nervous system by exploiting α-syn neuroprotective biology.
PubMed: 38917691
DOI: 10.1016/j.virol.2024.110141 -
Nucleic Acids Research Jun 2024Synucleinopathies, including dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA), are characterized by the presence of...
Synucleinopathies, including dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA), are characterized by the presence of α-synuclein (α-syn) aggregates in the central nervous system. Recent evidence suggests that the heterogeneity of synucleinopathies may be partly explained by the fact that patients may have different α-syn fibrillar polymorphs with structural differences. In this study, we identify nuclease resistant 2'fluoro-pyrimidine RNA aptamers that can differentially bind to structurally distinct α-syn fibrillar polymorphs. Moreover, we introduce a method, AptaFOOT-Seq, designed to rapidly assess the affinity of a mixture of these aptamers for different α-SYN fibrillar polymorphs using next-generation sequencing. Our findings reveal that the binding behavior of aptamers can be very different when they are tested separately or in the presence of other aptamers. In this case, competition and cooperation can occur, providing a higher level of information, which can be exploited to obtain specific 'footprints' for different α-Syn fibrillar polymorphs. Notably, these footprints can distinguish polymorphs obtained from patients with PD, DLB or MSA. This result suggests that aptaFOOT-Seq could be used for the detection of misfolded or abnormal protein conformations to improve the diagnosis of synucleinopathies.
PubMed: 38917326
DOI: 10.1093/nar/gkae544 -
Brain : a Journal of Neurology Jun 2024Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy...
Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by alpha-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, Alzheimer's disease is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analyzed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNAseq from the anterior cingulate cortex and determined differentially expressed genes (q-value < 0.05) in control (n = 81), Lewy body disease (n = 436), Alzheimer's disease (n = 53), and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis (WGCNA) to understand the pathways associated with each neuropathologically defined group. Lewy body disease cases had strong up-regulation of inflammatory pathways and down-regulation of metabolic pathways. The Lewy body disease cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the Lewy body disease cohorts consistently showed up-regulation for genes involved in protein folding and cytokine immune response, as well as down-regulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the Lewy body disease cases resulted in no additional changes. Some core inflammatory pathways were shared between Alzheimer's disease and Lewy body disease but with numerous disease-specific changes. Direct comparison of Lewy body disease cohorts versus Alzheimer's disease cases revealed strong enrichment of synaptic signaling, behavior, and neuronal system pathways. Females had a stronger response overall in both Lewy body and Alzheimer's disease, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined Lewy body disease and Alzheimer's disease cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.
PubMed: 38916996
DOI: 10.1093/brain/awae202 -
Journal of Neural Transmission (Vienna,... Jun 2024In pursuit of early therapeutic interventions for Parkinson's disease, the proposed SynNeurGe classification system integrates α-synuclein pathology (S),... (Review)
Review
In pursuit of early therapeutic interventions for Parkinson's disease, the proposed SynNeurGe classification system integrates α-synuclein pathology (S), neurodegeneration evidence (N), and pathogenic gene variants (G). This approach aims to address the disease's complexity and biological diversity. It suggests categorizing patients based on the presence or absence of α-synuclein pathology in tissues or cerebrospinal fluid, neurodegeneration indicators from specific imaging techniques, and identification of pathogenic gene variants associated with Parkinson's disease. The proposed system emphasizes the future need for precision medicine and aims to facilitate both basic and clinical research toward disease-modifying therapies. However, the authors stress that initial implementation should be confined to research settings, considering ethical implications and current limitations. Prospective validation of these criteria is deemed necessary to ensure their efficacy and ethical application in clinical practice.
PubMed: 38916622
DOI: 10.1007/s00702-024-02797-9