Onset Parkinson's Disease Research Articles

Association of Baseline Depression and Anxiety with Longitudinal Health Outcomes in Parkinson's Disease.

Anxiety and depression are common non-motor symptoms in Parkinson's disease (PD) but remain under-recognized and under-treated. To evaluate functional outcomes associated with baseline anxiety or depression and effects related to the initiation of new psychiatric treatment. We analyzed 7 years of data from patients with de novo PD enrolled in the Parkinson's Progression Markers Initiative. Longitudinal regression models evaluated the association between baseline anxiety and depression with Schwab and England (SE) and MDS-UPDRS total scores over time. Cox proportional hazard models assessed effects of baseline anxiety and depression on time to initiation of dopaminergic therapy. Piecewise linear regression models examined the association of treatment initiation for anxiety and depression with SE and MDS-UPDRS. 490 participants with baseline depression and anxiety data were included. Anxiety and depression were associated with lower SE (anxiety: β = -1.31, P = 0.038, depression: β = -1.96, P = 0.012, co-morbid: β = -2.70, P = 0.003) and higher MDS-UPDRS scores (anxiety: β = 5.37, P < 0.001, depression: β = 9.17, P < 0.001, co-morbid: β = 10.50, P < 0.001) longitudinally. Anxiety was associated with faster time to dopamine replacement therapy initiation (HR 1.30, 95% CI 1.03-1.66, P = 0.03). 16 participants with anxiety initiated treatment for anxiety, which was associated with subsequent lower levodopa daily dose (slope change = -218.49, P = 0.018). 10 participants with depression initiated treatment of depression, which was associated with reduced MDS-UPDRS total scores (slope change = -8.3, P < 0.001) and higher SE scores (slope change = 5.99, P = 0.004). Anxiety and depression at PD onset are associated with multiple negative longitudinal trajectories. However, preliminary findings suggest that anxiety and depression treatment may be linked with improved motor and non-motor outcomes.

β-Synuclein Intermediates α-Synuclein Neurotoxicity in Parkinson's Disease.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the world, and synuclein is closely related to the onset and progression of PD. Synuclein is considered a therapeutic target for PD. Recent studies have found that abnormal aggregation of α-synuclein (α-Syn) in the brains of PD patients leads to mitochondrial dysfunction and neuroinflammation. Research in the field of neuroscience has confirmed that β-synuclein (β-Syn) also plays a role in Parkinson's disease. However, there has been little research on the role mechanisms and interactions between β-Syn and α-Syn in PD. Therefore, the purpose of this study is to clarify the relationship between α-Syn, β-Syn, and PD and to explore the roles and interactions of β-Syn and α-Syn in PD.

IMMUnity Unveiled: A Translational NETwork for tackling PARKinson's Disease – IMMUPARKNET

Parkinson’s disease (PD) affects more than one million people in the EU. It currently has no definitive cure, meaning that patients rely only on symptomatic treatments, which themselves are burdened by side effects. The need for advancements in both knowledge and available treatments is thus strongly felt by patients, caregivers, and health operators. This unmet need sparked the idea of orchestrating a collaborative effort via a common network – IMMUPARKNET (The role of IMMUnity in tackling PARKinson’s disease through a Translational NETwork). The IMMUPARKNET COST Action focuses on challenges in PD and its related crosstalk with immune response. Although widely recognized, the role of immunity in the onset and development of PD is still unclear. The main goal of IMMUPARKNET is to fill this knowledge gap by establishing an innovative, interdisciplinary research network and fostering exchanges of expertise among specialists from different countries and institutions. As we gather scientists and clinicians who study immunity in PD and related fields, IMMUPARKNET will establish the first nucleus of a multidisciplinary ecosystem that aims to harmonize efforts and approaches, both in research and clinical practice, to boost the development of ground-breaking treatments for PD. Through meetings, training schools, webinars, position papers, and review manuscripts, IMMUPARKNET will lead fruitful exchanges of know-how among experts in the field. The IMMUPARKNET structure revolves around 5 working groups, with a total of 157 active members from 34 different countries. Of these active members, 58.5% are young researchers, while 67.5% come from Inclusiveness Target Countries (ITC - less research-intensive COST Members; https://www.cost.eu/about/members/). IMMUPARKNET output will facilitate the improved sharing and development of research resources, straightening the road to novel treatments and identifying where existing ones can be repurposed, all, ultimately and hopefully, finding a cure for PD.

Lead specifically declines tyrosine hydroxylase activity to induce the onset of Parkinson's disease through disrupting dopamine biosynthesis in fly models

Parkinson's disease (PD) is one of the fastest-growing neurodegenerative diseases and has been linked to the exposure to numerous environmental neurotoxins. Although lead (Pb) exposure has been related to the development of PD, the molecular target of Pb to cause the onset of PD is insufficiently investigated. Herein, we explored the effects of Pb exposure on behavior, pathophysiology, and gene expression of wild-type (WT) fly (Drosophila melanogaster) by comparison with its PD model. After exposure to Pb, the WT flies showed PD-like locomotor impairments and selective loss of dopaminergic (DAergic) neurons, displaying similar phenotypes to fly PD model (PINK1). Transcriptomic analysis showed the similarity in gene expression profiles between Pb treatment WT flies and PINK1 mutant flies. Moreover, Pb exposure resulted in endogenous dopamine deficits in WT flies. Analyses of gene expression and enzyme activity confirmed that Pb exposure reduced tyrosine hydroxylase (TH) activity and led to failure of dopamine synthesis. Furthermore, molecular dynamics simulation confirmed that Pb was adsorbed by TH and subsequently inhibited the enzymatic activity. Exogenous injection of L-dopa and melatonin could partially rescue the pathological phenotypes of Pb-exposed flies and PD fly model. Antagonist injection of microRNA-133, which negatively regulated the expression of TH gene, ultimately rescued in the manifestation of PD phenotypes in flies. Involvement of TH overexpression mutants of fly strongly promoted the resistance to Pb exposure and rescued both behavior and the number of DAergic neurons. Therefore, our study elucidates the Pb molecular target in dopamine pathway and mechanism underlying the risks of Pb exposure on the occurrence of PD at environmentally-relevant concentrations.

Identification of Prodromal Parkinson Disease: We May Be Able to But Should We?

Parkinson disease (PD) remains a progressive and incurable disease. Research over the past decade provides strong evidence of a detectible phase before the clinical diagnosis, known as the prodromal phase of PD (pPD). In this article, we review the debate about disclosure of risk of progression to PD and related disorders to individuals through the perspectives of the pillars of medical ethics: beneficence, nonmaleficence, autonomy, and justice. There is evidence that lifestyle modification may have positive effects on onset and progression of PD, providing justification of potential benefit. From a societal perspective, a diagnosis of pPD could allow targeted recruitment to disease-modifying trials. Regarding nonmaleficence, direct evidence that catastrophic reactions are scarce is largely derived from studies of monogenic conditions, which may not be generalizable. Diagnosis of PD can be traumatic, and appropriate communication and evaluation of circumstances to weigh up disclosure is crucial. Future research should therefore examine the potential harms of early and of false-positive diagnoses and specifically examine these matters in diverse populations. Autonomy balances the right to know and the right not to know, so an individualized patient-centered approach and shared decision-making is essential, acknowledging that knowledge of being in the prodromal phase could prolong autonomy in the longer term. Distributive justice brings focus toward health care and related planning at the individual and societal level and affects the search for disease modification in PD. We must acknowledge that waiting for established disease states is likely to be too little, too late and results in failures of expensive trials and wasted participant and researcher effort. Ultimately, clinicians must arrive at a decision with the patient that solicits and integrates patients' goals, taking into account their individual life circumstances, perspectives, and philosophies, recognizing that one size cannot fit all.

Diverse Functions of Parkin in Midbrain Dopaminergic Neurons.

Parkinson's disease (PD) is characterized by preferential degeneration of midbrain dopaminergic neurons that contributes to its typical clinical manifestation. Mutations in the parkin gene (PARK2) represent a relatively common genetic cause of early onset PD. Parkin has been implicated in PINK1-dependent mitochondrial quantity control by targeting dysfunctional mitochondria to lysosomes via mitophagy. Recent evidence suggests that parkin can be activated in PINK1-independent manner to regulate synaptic function in human dopaminergic neurons. Neuronal activity triggers CaMKII-mediated activation of parkin and its recruitment to synaptic vesicles where parkin promotes binding of synaptojanin-1 to endophilin A1 and facilitates vesicle endocytosis. In PD patient neurons, disruption of this pathway on loss of parkin leads to defective recycling of synaptic vesicles and accumulation of toxic oxidized dopamine that at least in part explains preferential vulnerability of midbrain dopaminergic neurons. These findings suggest a convergent mechanism for PD-linked mutations in parkin, synaptojanin-1, and endophilin A1 and highlight synaptic dysfunction as an early pathogenic event in PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Air pollution, greenspace exposure and risk of Parkinson's disease: a prospective study of 441,462 participants.

The current understandings of the relationship between air pollution (AP), greenspace exposure and Parkinson's Disease (PD) remain inconclusive. We engaged 441,462 participants from the UK Biobank who were not diagnosed with PD. Utilizing Cox proportional hazard regression model, relationships between AP [nitrogen dioxide (NO2), and nitrogen oxides (NOX), particulate matter < 2.5μm in aerodynamic diameter(PM2.5), coarse particulate matter between 2.5μm and 10μm in aerodynamic diameter(PM2.5-10), particulate matter < 10μm in aerodynamic diameter(PM10)], greenspace exposure, and PD risk were determined independently. Our analyses comprised three models, adjusted for covariates, and affirmed through six sensitivity analyses to bolster the robustness of our findings. Moreover, mediation analysis was deployed to discern the mediating effect of AP between greenspaces and PD. During a median follow-up of 12.23years (5,574,293 person-years), there were 3,293 PD events. Each interquartile (IQR) increment in NO2 and PM10 concentrations were associated with 10% and 8% increase in PD onset risk, while the increases in NOX, PM2.5 and PM2.5-10 were not associated with PD risk. Additionally, greenspace may safeguard by reducing NO2 and PM10 levels, with the effect mediated by NO2 and PM10 in greenspace-PD relationship. Our findings indicate that an IQR increase in ambient NO2 and PM10 concentrations was associated with risk of PD development, while other pollutants (NOX, PM2.5 and PM2.5-10) were not associated with PD risk. Firstly, we find that augmented exposure to greenspace was associated with the lower PD risk by reducing NO2 and PM10 levels.

Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD+/-), with further classification of PDRBD+ based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. PDRBD+ exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD-, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD+<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD+ even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD.

High Mobility Group Box 1 Protein: A Plausible Therapeutic Molecular Target in Parkinson's Disease.

Parkinson's disease (PD) is a widespread neurodegenerative disorder that exerts a broad variety of detrimental effects on people's health. Accumulating evidence suggests that mitochondrial dysfunction, neuroinflammation, α-synuclein aggregation and autophagy dysfunction may all play a role in the development of PD. However, the molecular mechanisms behind these pathophysiological processes remain unknown. Currently, research in PD has focussed on high mobility group box 1 (HMGB1), and different laboratory approaches have shown promising outcomes to some level for blocking HMGB1. Given that HMGB1 regulates mitochondrial dysfunction, participates in neuroinflammation, and modulates autophagy and apoptosis, it is hypothesised that HMGB1 has significance in the onset of PD. In the current review, research targeting multiple roles of HMGB1 in PD pathology was integrated, and the issues that need future attention for targeted therapeutic approaches are mentioned.

The Parkinson's Puzzle Box.

Women and those with younger onset Parkinson's Disease (YOPD) are typically diagnosed later and face unique situations and challenges. This essay aims to raise awareness of the difficulties in diagnosing YOPD and the need for a personalised approach to care for women with YOPD. Two professional women with YOPD (academic physiotherapist and practicing dentist) and a female neurologist (clinician academic) came together to write a narrative essay on their personal experience and perspectives in relation to women and YOPD. The essay outlines how the experience of diagnosis is likened to a complex puzzle box with many interlocking components that are hidden and difficult to solve. The concerns of the women about their identity, work, family and the future, with most supports targeting those that are older and retired are outlined. It is concluded that YOPD is a complex puzzle to solve, but can be done by understanding all the intricate interlocking components of the puzzle and combined with greater awareness could lead to earlier diagnosis and the delivery of successful person-centred care. People with lived experience were involved in the essay conception and writing.

P.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

Impulse control disorders and use of dopamine agonists in early onset Parkinson's disease.

Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD. We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists. A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance (p = 0.011). ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.

Soot nanoparticles promote ferroptosis in dopaminergic neurons via alteration of m6A RNA methylation in Parkinson’s disease

Soot nanoparticles (SNPs) are black carbon prevalent in atmospheric environment with significant impacts on public health, leading to neurodegenerative diseases including development of Parkinson’s disease (PD). This study investigated the effects of SNPs exposure on PD symptoms, employing both in vivo and in vitro PD models. In the in vivo experiments, animal behavior assessments showed that SNPs exposure exacerbated motor and cognitive impairments in PD mice. Molecular biology techniques further unveiled that SNPs aggravated degeneration of dopaminergic neurons. In vitro experiments revealed that SNPs exposure intensified ferroptosis of PD cells by increasing reactive oxygen species and iron ion levels, while reducing glutathione levels and mitochondrial membrane potential. Sequencing tests indicated elevated N6-methyladenosine (m6A) alteration of the ferroptosis-related protein, acyl-CoA synthetase long chain family member 4 (ACSL4). This study demonstrates that SNPs may exacerbate the onset and progression of PD by recruiting YTH domain-containing family protein 1 (YTHDF1) protein, enhancing m6A methylation in the ACSL4 5′UTR, amplifying ACSL4 protein expression, and accelerating the ferroptosis process in dopaminergic neurons. These molecular mechanisms underlying SNPs exacerbation of PD development may provide crucial insights for formulating environmental safety regulations and potential therapeutic strategies addressing PD in populations residing in regions with varied air quality.

Role of ATP10B in Parkinson disease in a cohort from southern Spain

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion.

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson's disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

Association between Parkinson disease and selenium levels in the body: A systematic review and meta-analysis.

Parkinson disease (PD) is a common neurodegenerative disorder, but its pathogenesis is still not entirely understood. While some trace elements, such as selenium, iron, and copper, are considered pivotal in PD onset due to their role in oxidative stress, the association between selenium concentrations and PD susceptibility remains ambiguous. A systematic review and meta-analysis was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and framed by the Patient, Intervention, Comparison, Outcome paradigm. Data were sourced from 4 prominent electronic databases: PubMed, Embase, Web of Science, and Cochrane Library. Eligible studies must have had a PD case group and a control group, both of which presented data on selenium concentrations. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Of 1541 initially identified articles, 12 studies comprising a total of 597 PD cases and 733 controls were selected for the meta-analysis. Pronounced heterogeneity was observed among these studies. When assessing blood selenium levels, no significant difference was found between patients with PD and the controls. However, when examining the cerebrospinal fluid, selenium levels in PD patients were significantly elevated compared to controls (standard mean difference = 1.21, 95% CI 0.04-2.39, P < .05). Subgroup analyses, sensitivity analyses, and evaluation of publication bias were performed to ensure data robustness. Elevated selenium levels in cerebrospinal fluid may be associated with a higher risk of Parkinson. Further prospective research is required to solidify this potential link and to offer avenues for novel therapeutic interventions or preventive measures.

Optimization of the Preparation Process of Glucuronomannan Oligosaccharides and Their Effects on the Gut Microbiota in MPTP-Induced PD Model Mice.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and accumulating evidence suggests a link between dysbiosis of the gut microbiota and the onset and progression of PD. In our previous investigations, we discovered that intraperitoneal administration of glucuronomannan oligosaccharides (GMn) derived from Saccharina japonica exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. However, the complicated preparation process, difficulties in isolation, and remarkably low yield have constrained further exploration of GMn. In this study, we optimized the degradation conditions in the preparation process of GMn through orthogonal experiments. Subsequently, an MPTP-induced PD model was established, followed by oral administration of GMn. Through a stepwise optimization, we successfully increased the yield of GMn, separated from crude fucoidan, from 1~2/10,000 to 4~8/1000 and indicated the effects on the amelioration of MPTP-induced motor deficits, preservation of dopamine neurons, and elevation in striatal neurotransmitter levels. Importantly, GMn mitigated gut microbiota dysbiosis induced by MPTP in mice. In particular, GM2 significantly reduced the levels of Akkermansia, Verrucomicrobiota, and Lactobacillus, while promoting the abundance of Roseburia and Prevotella compared to the model group. These findings suggest that GM2 can potentially suppress PD by modulating the gut microbiota, providing a foundation for the development of a novel and effective anti-PD marine drug.

Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort.

Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD. Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk. In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results. This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.

14-3-3τ as a Modulator of Early α-Synuclein Multimerization and Amyloid Formation.

The aggregation of α-synuclein (αS) plays a key role in Parkinson's disease (PD) etiology. While the onset of PD is age-related, the cellular quality control system appears to regulate αS aggregation throughout most human life. Intriguingly, the protein 14-3-3τ has been demonstrated to delay αS aggregation and the onset of PD in various models. However, the molecular mechanisms behind this delay remain elusive. Our study confirms the delay in αS aggregation by 14-3-3τ, unveiling a concentration-dependent relation. Utilizing microscale thermophoresis (MST) and single-molecule burst analysis, we quantified the early αS multimers and concluded that these multimers exhibit properties that classify them as nanoscale condensates that form in a cooperative process, preceding the critical nucleus for fibril formation. Significantly, the αS multimer formation mechanism changes dramatically in the presence of scaffold protein 14-3-3τ. Our data modeling suggests that 14-3-3τ modulates the multimerization process, leading to the creation of mixed multimers or co-condensates, comprising both αS and 14-3-3τ. These mixed multimers form in a noncooperative process. They are smaller, more numerous, and distinctively not on the pathway to amyloid formation. Importantly, 14-3-3τ thus acts in the very early stage of αS multimerization, ensuring that αS does not aggregate but remains soluble and functional. This offers long-sought novel entries for the pharmacological modulation of PD.

Human Nasal Inferior Turbinate-Derived Neural Stem Cells Improve the Niche of Substantia Nigra Par Compacta in a Parkinson’s Disease Model by Modulating Hippo Signaling

Background:Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases, following Alzheimer’s disease. The onset of PD is characterized by the loss of dopaminergic neurons in the substantia nigra. Stem cell therapy has great potential for the treatment of neurodegenerative diseases, and human nasal turbinate-derived stem cells (hNTSCs) have been found to share some characteristics with mesenchymal stem cells. Although the Hippo signaling pathway was originally thought to regulate cell size in organs, recent studies have shown that it can also control inflammation in neural cells.Methods:Dopaminergic neuron-like cells were differentiated from SH-SY5Y cells (DA-Like cells) and treated with 1-Methyl-4-phenylpyridinium iodide to stimulate Reactive oxidative species (ROS) production. A transwell assay was conducted to validate the effect of hNTSCs on the Hippo pathway. We generated an MPTP-induced PD mouse model and transplanted hNTSCs into the substantia nigra of PD mice via stereotaxic surgery. After five weeks of behavioral testing, the brain samples were validated by immunoblotting and immunostaining to confirm the niche control of hNTSCs.Results:In-vitro experiments showed that hNTSCs significantly increased cell survival and exerted anti-inflammatory effects by controlling ROS-mediated ER stress and hippocampal signaling pathway factors. Similarly, the in-vivo experiments demonstrated an increase in anti-inflammatory effects and cell survival rate. After transplantation of hNTSCs, the PD mouse model showed improved mobility and relief from PD symptoms.Conclusion:hNTSCs improved the survival rate of dopaminergic neurons by manipulating the hippocampal pathway through Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding motif (TAZ) by reducing inflammatory cytokines. In this study, we found that controlling the niche of hNTSCs had a therapeutic effect on PD lesions.