Parkinson's Disease Brain Research Articles

Multi-Targeting Macrocyclic Peptides as Nanomolar Inhibitors of Self- and Cross-Seeded Amyloid Self-Assembly of α-Synuclein.

Amyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies.

Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

The Role of Microglia in Parkinson's Disease and Possible Therapeutic Targets

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to significant motor and non-motor symptoms. Recent research highlights the critical role of microglia, the resident immune cells of the central nervous system, in the pathogenesis and progression of PD. Microglia contribute to neuroinflammation through the release of pro-inflammatory cytokines and reactive oxygen species, exacerbating neuronal damage. Moreover, α-synuclein aggregates, a hallmark of PD, activate microglia, further promoting inflammation and neurodegeneration. This review explores the dual role of microglia in PD, encompassing both their neuroprotective functions and their contribution to neuroinflammation. We discuss the molecular mechanisms underlying microglial activation and their interactions with astrocytes, another crucial glial cell type. The review also examines potential therapeutic targets aimed at modulating microglial activity to mitigate neuroinflammation and slow the progression of PD. Current therapeutic strategies predominantly focus on symptomatic relief through dopaminergic medications. However, emerging therapies targeting microglial activation, such as anti-inflammatory drugs, immunomodulators, and novel agents like metabotropic glutamate receptor 5 (mGluR5) modulators, offer promising avenues for disease modification. Understanding the complex interplay between microglia and other cellular components in the PD brain is essential for developing effective treatments that address the underlying pathophysiological mechanisms of the disease.

14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity.

Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein with chaperone-like activity that regulates αsyn folding. 14-3-3θ overexpression reduces αsyn aggregation, transmission between cells, and neuronal loss, while 14-3-3 inhibition promotes αsyn pathology. We previously observed increased 14-3-3θ phosphorylation at serine 232 in human PD and DLB brains. Here we examine 14-3-3θ phosphorylation's effects on αsyn aggregation and toxicity. Using a paracrine αsyn model, we found that the non-phosphorylatable S232A 14-3-3θ protected while the phosphomimetic S232D 14-3-3θ failed to protect against αsyn paracrine toxicity. The S232A mutant reduced oligomerization of released αsyn while the S232D mutant did not. The S232D mutant showed significant reduction in αsyn binding compared to wildtype or S232A 14-3-3θ. Using knock-in mouse models expressing the S232A or S232D mutation in the cortex and hippocampus, we examined the impact of S232 phosphorylation on αsyn aggregation in the αsyn preformed fibril (PFF) model. Primary neurons from S232D mice showed increased αsyn inclusion formation compared to neurons from Cre control mice upon PFF treatment. In contrast, neurons from S232A mice showed reduced αsyn inclusions. αSyn PFF injection into the dorsolateral striatum induced higher αsyn inclusion numbers in the sensorimotor cortex of S232D mice compared to Cre control mice. In conclusion, 14-3-3θ phosphorylation at S232 interrupts the ability of 14-3-3θ to bind and regulate αsyn aggregation. Increased 14-3-3θ phosphorylation observed in human PD and DLB likely accelerates neurodegeneration in these disorders.

Antioxidative and Anticancer Potential of Luteolin: A Comprehensive Approach Against Wide Range of Human Malignancies

ABSTRACTLuteolin is widely distributed phytochemical, a flavonoid, in kingdom plantae. Luteolin with potential antioxidant activity prevent ROS‐induced damages and reduce oxidative stress which is mainly responsible in pathogenesis of many diseases. Several chemo preventive activities and therapeutic benefits are associated with luteolin. Luteolin prevents cancer via modulation of numerous pathways, that is, by inactivating proteins; such as procaspase‐9, CDC2 and cyclin B or upregulation of caspase‐9 and caspase‐3, cytochrome C, cyclin A, CDK2, and APAF‐1, in turn inducing cell cycle arrest as well as apoptosis. It also enhances phosphorylation of p53 and expression level of p53‐targeted downstream gene. By Increasing BAX protein expression; decreasing VEGF and Bcl‐2 expression it can initiate cell cycle arrest and apoptosis. Luteolin can stimulate mitochondrial‐modulated functions to cause cellular death. It can also reduce expression levels of p‐Akt, p‐EGFR, p‐Erk1/2, and p‐STAT3. Luteolin plays positive role against cardiovascular disorders by improving cardiac function, decreasing the release of inflammatory cytokines and cardiac enzymes, prevention of cardiac fibrosis and hypertrophy; enhances level of CTGF, TGFβ1, ANP, Nox2, Nox4 gene expressions. Meanwhile suppresses TGFβ1 expression and phosphorylation of JNK. Luteolin helps fight diabetes via inhibition of alpha‐glucosidase and ChE activity. It can reduce activity levels of catalase, superoxide dismutase, and GS4. It can improve blood glucose, insulin, HOMA‐IR, and HbA1c levels. This review is an attempt to elaborate molecular targets of luteolin and its role in modulating irregularities in cellular pathways to overcome severe outcomes during diseases including cancer, cardiovascular disorders, diabetes, obesity, inflammation, Alzheimer's disease, Parkinson's disease, hepatic disorders, renal disorders, brain injury, and asthma. As luteolin has enormous therapeutic benefits, it could be a potential candidate in future drug development strategies.

ROS Regulation in CNS Disorder Therapy: Unveiling the Dual Roles of Nanomedicine.

The treatment of brain diseases has always been the focus of attention. Due to the presence of the blood-brain barrier (BBB), most small molecule drugs are difficult to reach the brain, leading to undesirable therapeutic outcomes. Recently, nanomedicines that can cross the BBB and precisely target lesion sites have emerged as thrilling tools to enhance the early diagnosis and treat various intractable brain disorders. Extensive research has shown that reactive oxygen species (ROS) play a crucial role in the occurrence and progression of brain diseases, including brain tumors and neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, stroke, or traumatic brain injury, making ROS a potential therapeutic target. In this review, on the structure and function of BBB as well as the mechanisms are first elaborated through which nanomedicine traverses it. Then, recent studies on ROS production are summarizedthrough photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT) for treating brain tumors, and ROS depletion for treating NDDs. This provides valuable guidance for the future design of ROS-targeted nanomedicines for brain disease treatment. The ongoing challenges and future perspectives in developing nanomedicine-based ROS management for brain diseases are also discussed and outlined.

Leucencephalopathy in Patients with Parkinson's Disease and Deep Brain Stimulation.

Leucencephalopathy (LE) is often detected on magnetic resonance imaging in elderly patients. These white matter lesions may interfere with lead trajectories for deep brain stimulation (DBS) in patients with Parkinson's disease (PD) and are associated with complications after DBS surgery. This study was conducted to assess the incidence of LE in PD patients and to evaluate correlations with complications after DBS surgery. A consecutive cohort of PD patients who underwent DBS surgery in the subthalamic nucleus (STN-DBS) was retrospectively analyzed. The presence and extent of LE were quantified using the Fazekas scale. Postoperative complications were extracted from the medical records. DBS efficacy was calculated using the side-specific motor symptom ratio (Unified Parkinson's Disease Rating Scale, Part III, postoperative stimulation ON/medication off divided by preoperative medication off) at 1-year follow-up. A total of 135 PD patients were included in the study. LE was detected in 35.6% (48/135) of the patients. In 87.7% (57/65), LE was mild, in 10.7% (7/65) moderate, and in 1.6% (1/65) severe. A higher incidence of mild to moderate LE did not correlate with postoperative hemorrhage or postoperative infection. There was no correlation of LE with stimulation efficacy (r = -0.05, P = 0.69) or with surgical index (r = -0.10, P = 0.35). Neither was the presence of mild to moderate LE associated with an increased risk for surgical complications, nor did it negatively impact the long-term improvement in motor function after DBS surgery in PD patients. Therefore, mild to moderate LE should not be considered a contraindication for DBS.

Functional Brain Network Disruptions in Parkinson's Disease: Insights from Information Theory and Machine Learning.

Objectives: This study investigates disruptions in functional brain networks in Parkinson's Disease (PD), using advanced modeling and machine learning. Functional networks were constructed using the Nonlinear Autoregressive Distributed Lag (NARDL) model, which captures nonlinear and asymmetric dependencies between regions of interest (ROIs). Key network metrics and information-theoretic measures were extracted to classify PD patients and healthy controls (HC), using deep learning models, with explainability methods employed to identify influential features. Methods: Resting-state fMRI data from the Parkinson's Progression Markers Initiative (PPMI) dataset were used to construct NARDL-based networks. Metrics, such as Degree, Closeness, Betweenness, and Eigenvector Centrality, along with Network Entropy and Complexity, were analyzed. Convolutional Neural Networks (CNNs), Recurrent Neural Networks (RNNs), and Long Short-Term Memory (LSTM) models, classified PD and HC groups. Explainability techniques, including SHAP and LIME, identified significant features driving the classifications. Results: PD patients showed reduced Closeness (22%) and Betweenness Centrality (18%). CNN achieved 91% accuracy, with Network Entropy and Eigenvector Centrality identified as key features. Increased Network Entropy indicated heightened randomness in PD brain networks. Conclusions: NARDL-based analysis with interpretable deep learning effectively distinguishes PD from HC, offering insights into neural disruptions and potential personalized treatments for PD.

Nonmotor Manifestations of Idiopathic Parkinson's Disease and Its Correlation with the Severity and Duration of the Disease: A Cross-sectional Study.

Parkinson's disease (PD) is a neurodegenerative disorder that is common in individuals over the age of 50 years, affecting about 1% of the population. Nonmotor symptoms (NMS) are a common occurrence in PD, but they are often ignored by motor symptoms. Studies have shown that NMS in PD show a significant impact on quality of life. The introduction of tools like nonmotor symptoms scale (NMSS) and unified Parkinson's disease rating scale (UPDRS) that have a specific nonmotor domain will assist in defining research and therapy to enhance the early identification and management of NMS in the affected population. (1) To evaluate the prevalence of NMS in different stages of idiopathic Parkinson's disease. (2) To correlate the prevalence of NMS with the duration and severity of the disease. The study involved 80 individuals who visited the Movement Disorder Clinic at Stanley Medical College and Hospital in Chennai and were diagnosed with idiopathic Parkinson's disease, which was in agreement with the United Kingdom Parkinson's Disease (UK PD) Brain Bank criteria. Out of the 80 study participants, 63.7% (n = 51) were male and 36.3% (n = 29) were female. In our study, the mean age of patients was 63.1 ± 7.01 years. The study population was predominantly aged 50-60 years (n = 36), followed by 61-70 years (n = 30), which made up more than 80% of the population. Age group of >71 years constituted only 17.5% (n = 14). Majority of the patients, that is, 42.5% (n = 34) were in stage 3 of Hoehn and Yahr (H&Y) staging. The mean and mode of H&Y stage were 2.7 ± 0.9 and 3, respectively. The mean duration of disease was 4.7 ± 2.7 years. The mean UPDRS score was 66 ± 24.5. The mean NMSS score was 32 ± 10.18. NMSs are found to be highly prevalent among Indian patients with PD according to this study. The nonmotor symptom questionnaire aids in early detection and recognition of nonmotor symptoms in PD patients.

Relaxometry network based on MRI R2⁎ mapping revealing brain iron accumulation patterns in Parkinson's disease

BackgroundExcessive iron accumulation in the brain has been implicated in Parkinson's disease (PD). However, the patterns and probable sequences of iron accumulation across the PD brain remain largely unknown. This study aimed to explore the sequence of iron accumulation across the PD brain using R2* mapping and a relaxometry covariance network (RCN) approach. MethodsR2* quantification maps were obtained from PD patients (n = 34) and healthy controls (n = 25). RCN was configured on R2* maps to identify covariance differences in iron levels between the two groups. Regions with excessive iron accumulation and large covariance changes in PD patients compared to controls were defined as propagators of iron. In the PD group, causal RCN analysis was performed on the R2* maps sequenced according to disease duration to investigate the dynamics of iron accumulations from the propagators. The associations between individual connections of the RCN and clinical information were analyzed in PD patients. ResultsThe left substantia nigra pars reticulata (SNpr), left substantia nigra pars compacta (SNpc), and lobule VII of the vermis (VER7) were identified as primary regions for iron accumulation and propagation (propagator). As the disease duration increased, iron accumulation in these three propagators demonstrated positive causal effects on the bilateral pallidum, bilateral gyrus rectus, right middle frontal gyrus, and medial and anterior orbitofrontal cortex (OFC). Furthermore, individual connections of VER7 with the left gyrus rectus and anterior OFC were positively associated with disease duration. ConclusionsOur results indicate that the aberrant iron accumulation in PD involves several regions, mainly starts from the SN and cerebellum and extends to the pallidum and cortices. These findings provide preliminary information on sequences of iron accumulation in PD, which may advance our understanding of the disease.

A systematic review of progenitor survival and maturation in Parkinsonian models.

Stem cell-based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source. Unlike current therapeutic options for patients, this approach has the potential to provide long-term stem cell-derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients. The ultimate clinical success of stem cell-derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain. Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies, the aim of this systematic review was to assess these parameters in human stem cell-derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease. A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024. After screening, 76 articles were included in the analysis from which 178 separate transplant studies were identified. From these, graft survival could be assessed in 52 studies and differentiation in 129 studies. Overall, we found that graft survival ranged from < 1% to 500% of cells transplanted, with a median of 51% of transplanted cells surviving in the brain; while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%. This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell-derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.

Towards a Non-pharmacological Intervention on Apathy in Korsakoff's Syndrome: A Systematic Narrative Review Across Different Clinical Conditions.

Apathy is a quantitative reduction of goal-directed activity, which can be observed in relation to behavior, cognition, emotions and social interaction. It is an invalidating behavioral symptom that is frequently present across different psychiatric conditions and neurocognitive disorders including Korsakoff's Syndrome (KS). In fact, apathy is one of the most severe behavioral symptoms of KS and has a major impact on the lives of patients and their relatives and other informal caregivers. However, guidelines for the treatment of apathy in KS are currently not available. This systematic narrative review provides a transdiagnostic overview of the effectiveness of different types of non-pharmacological interventions on apathy across different study populations that at symptom-level share characteristics with KS. This evidence may inform the development of an intervention targeting apathy in KS. The included study populations are dementia (due to Alzheimer's disease, or vascular dementia), Parkinson's disease, schizophrenia and traumatic brain injury. Through a stepped selection approach and with regard to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 22 systematic reviews and 32 empirical articles on the non-pharmacological treatment of apathy were identified. The results show a variety of effective non-pharmacological interventions on apathy. In conditions with severe cognitive impairments, successful interventions did not rely on intrinsic motivation, self-monitoring, or illness insight of the patients, but depend on external stimulation and behavioral activation. Since apathy is a multidimensional construct, identification of the extent and type of apathetic behavior before starting an intervention is highly recommended. Furthermore, it is important to adjust the treatment to the patients' personal interests and needs and embedded in daily care. CRD42022298464 (PROSPERO).

Interplays Between Matrix Metalloproteinases and Neurotropic Viruses: An Overview.

Matrix metalloproteinases (MMPs) are a diverse group of proteases involved in various physiological and pathological processes through modulation of extracellular matrix (ECM) components, cytokines, and growth factors. In the central nervous system (CNS), MMPs play a major role in CNS development, plasticity, repair, and reorganisation contributing to learning, memory, and neuroimmune response to injury. MMPs are also linked to various neurological disorders such as Alzheimer's disease, Parkinson's disease, cerebral aneurysm, stroke, epilepsy, multiple sclerosis, and brain cancer suggesting these proteases as key regulatory factors in the nervous system. Moreover, MMPs have been involved in the pathogenesis of neurotropic viral infections via dysregulation of various cellular processes, which may highlight these factors as potential targets for the treatment and control of neurological complications associated with viral pathogens. This review provides an overview of the roles of MMPs in various physiological processes of the CNS and their interactions with neurotropic viral pathogens.

Single-cell transcriptomic and proteomic analysis of Parkinson's disease brains.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, and recent evidence suggests that pathogenesis may be in part mediated by inflammatory processes, the molecular and cellular architectures of which are largely unknown. To identify and characterize selectively vulnerable brain cell populations in PD, we performed single-nucleus transcriptomics and unbiased proteomics to profile the prefrontal cortex from postmortem human brains of six individuals with late-stage PD and six age-matched controls. Analysis of nearly 80,000 nuclei led to the identification of eight major brain cell types, including elevated brain-resident T cells in PD, each with distinct transcriptional changes in agreement with the known genetics of PD. By analyzing Lewy body pathology in the same postmortem brain tissues, we found that α-synuclein pathology was inversely correlated with chaperone expression in excitatory neurons. Examining cell-cell interactions, we found a selective abatement of neuron-astrocyte interactions and enhanced neuroinflammation. Proteomic analyses of the same brains identified synaptic proteins in the prefrontal cortex that were preferentially down-regulated in PD. By comparing this single-cell PD dataset with a published analysis of similar brain regions in Alzheimer's disease (AD), we found no common differentially expressed genes in neurons but identified many shared differentially expressed genes in glial cells, suggesting that the disease etiologies, especially in the context of neuronal vulnerability, in PD and AD are likely distinct.

ApoE: The Non-Protagonist Actor in Neurological Diseases.

Apolipoprotein E (APOE = gene, ApoE = protein) is a glycoprotein involved in the biological process of lipid transportation and metabolism, contributing to lipid homeostasis. APOE has been extensively studied for its correlation with neurodegenerative diseases, in particular Alzheimer's disease (AD), where the possession of the epsilon 4 (E4) allele is established as a risk factor for developing AD in non-familiar sporadic forms. Recently, evidence suggests a broad involvement of E4 also in other neurological conditions, where it has been shown to be a predictive marker for worse clinical outcomes in Parkinson's disease (PD), brain trauma, and disturbances of consciousness. The mechanisms underlying these associations are complex and involve amyloid-β (Aβ) peptide accumulation and neuroinflammation, although many others have yet to be identified. The aim of this review is to overview the current knowledge on ApoE as a non-protagonist actor in processes underlying neurodegenerative diseases and its clinical significance in AD, PD, acquired brain trauma, and Disorders of Consciousness (DoC). Ethical implications of genetic testing for APOE variants and information disclosure will also be briefly discussed.

Bidirectional interaction between IL and 17A/IL-17RA pathway dysregulation and α-synuclein in the pathogenesis of Parkinson’s disease

Parkinson’s disease (PD) pathogenesis is characterized by α-synuclein (α-syn) pathology, which is influenced by various factors such as neuroinflammation and senescence. Increasing evidence has suggested a pivotal role for Interleukin-17A(IL-17A) and Interleukin-17 Receptor A (IL-17RA) in PD, yet the trigger and impact of IL-17A/IL-17RA activation in PD remains elusive. This study observed an age-related increase in IL-17A and IL-17RA in the human central nervous system, accompanied by increased α-syn and senescence biomarkers. Interestingly, both levels of IL-17A and IL-17RA in PD patients were significantly elevated compared to age-matched controls, wherein the IL-17A was mainly present in neurons. This abnormal neuronal IL-17A activation in the PD brain was recapitulated in α-syn mouse models. Correspondingly, administration of recombinant IL-17A exacerbated pathological α-syn in both neuron and mouse models. Furthermore, IL-17A/IL-17RA pathway interventions via blocking antibody or shRNA-mediated knockdown can mitigate the effects of pathological α-syn. This study reveals an interplay between dysregulation of the IL-17A/IL-17RA pathway and α-syn, suggesting that regulating the IL-17A/IL-17RA pathway could modify PD progression by disrupting the detrimental cycle.

Integrative Metabolome and Proteome Analysis of Cerebrospinal Fluid in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Recent studies have highlighted the significant role of cerebrospinal fluid (CSF) in reflecting pathophysiological PD brain conditions by analyzing the components of CSF. Based on the published literature, we created a single network with altered metabolites in the CSF of patients with PD. We analyzed biological functions related to the transmembrane of mitochondria, respiration of mitochondria, neurodegeneration, and PD using a bioinformatics tool. As the proteome reflects phenotypes, we collected proteome data based on published papers, and the biological function of the single network showed similarities with that of the metabolomic network. Then, we analyzed the single network of integrated metabolome and proteome. In silico predictions based on the single network with integrated metabolomics and proteomics showed that neurodegeneration and PD were predicted to be activated. In contrast, mitochondrial transmembrane activity and respiration were predicted to be suppressed in the CSF of patients with PD. This review underscores the importance of integrated omics analyses in deciphering PD's complex biochemical networks underlying neurodegeneration.

Brain-Region-Specific Differences in Protein Citrullination/Deimination in a Pre-Motor Parkinson's Disease Rat Model.

The detection of early molecular mechanisms and potential biomarkers in Parkinson's disease (PD) remains a challenge. Recent research has pointed to novel roles for post-translational citrullination/deimination caused by peptidylarginine deiminases (PADs), a family of calcium-activated enzymes, in the early stages of the disease. The current study assessed brain-region-specific citrullinated protein targets and their associated protein-protein interaction networks alongside PAD isozymes in the 6-hydroxydopamine (6-OHDA) induced rat model of pre-motor PD. Six brain regions (cortex, hippocampus, striatum, midbrain, cerebellum and olfactory bulb) were compared between controls/shams and the pre-motor PD model. For all brain regions, there was a significant difference in citrullinated protein IDs between the PD model and the controls. Citrullinated protein hits were most abundant in cortex and hippocampus, followed by cerebellum, midbrain, olfactory bulb and striatum. Citrullinome-associated pathway enrichment analysis showed correspondingly considerable differences between the six brain regions; some were overlapping for controls and PD, some were identified for the PD model only, and some were identified in control brains only. The KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in PD brains only were associated with neurological, metabolic, immune and hormonal functions and included the following: "Axon guidance"; "Spinocerebellar ataxia"; "Hippo signalling pathway"; "NOD-like receptor signalling pathway"; "Phosphatidylinositol signalling system"; "Rap1 signalling pathway"; "Platelet activation"; "Yersinia infection"; "Fc gamma R-mediated phagocytosis"; "Human cytomegalovirus infection"; "Inositol phosphate metabolism"; "Thyroid hormone signalling pathway"; "Progesterone-mediated oocyte maturation"; "Oocyte meiosis"; and "Choline metabolism in cancer". Some brain-region-specific differences were furthermore observed for the five PAD isozymes (PADs 1, 2, 3, 4 and 6), with most changes in PAD 2, 3 and 4 when comparing control and PD brain regions. Our findings indicate that PAD-mediated protein citrullination plays roles in metabolic, immune, cell signalling and neurodegenerative disease-related pathways across brain regions in early pre-motor stages of PD, highlighting PADs as targets for future therapeutic avenues.

α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice

Abnormal accumulation of insoluble α-synuclein (α-Syn) inclusions in neurons, neurites, and glial cells is the defining neuropathology of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Accumulation of α-Syn inclusions in the amygdala has been well-documented in post-mortem studies of PD and DLB brains, as well as preclinical animal models of these conditions. Though α-Syn pathology is closely associated with neurodegeneration, there is a poor correlation between neuronal loss in the amygdala and the clinical features of PD and DLB. Moreover, functional interaction between the cerebral cortex and the amygdala is critical to regulating emotion, motivation, and social behaviors. The cortico-amygdala functional interaction is likely to be disrupted by the development of α-Syn pathology in the brain. Thus, we hypothesize that neuronal α-Syn inclusions disrupt cortical modulation of the amygdala circuits and are sufficient to drive social behavioral deficits. In the present work, we designed a series of longitudinal studies to rigorously measure the time courses of neurodegeneration, functional impairment of cortico-amygdala connectivity, and development of amygdala-dependent social behavioral deficits to test this hypothesis. We injected α-Syn preformed fibrils (PFFs) into the dorsal striatum to induce α-Syn aggregation in the amygdala and the medial prefrontal cortex (mPFC) of C57BL6 mice of both sexes, followed by a detailed analysis of temporal development of α-Syn pathology, synaptic deficits, and neuronal loss in the amygdala, as well as behavioral deficits at 3–12 months post injections. Development of α-Syn inclusions caused losses of cortical axon terminals and cell death in the basolateral amygdala (BLA) at 6- and 12-months post injections, respectively. At a relatively early stage of 3 months post injections, the connection strength of the mPFC-BLA synapse was decreased in PFFs-injection mice compared to controls. Meanwhile, the PFFs-injected mice showed impaired social interaction behavior, which was rescued by chemogenetic stimulation of mPFC-BLA connections. Altogether, we presented a series of evidence to delineate circuit events in the amygdala associated with the accumulation of α-Syn inclusions in the mouse brain, highlighting that functional impairment of the amygdala is sufficient to cause social behavior deficits. The present work further suggests that early circuit modulation could be an effective approach to alleviate symptoms associated with α-Syn pathology, necessitating studies of functional consequences of α-Syn aggregation.

Exploring chitosan nanoparticles for enhanced therapy in neurological disorders: a comprehensive review.

Chitosan nanoparticles have emerged as a promising therapeutic platform for treating neurological disorders due to their biocompatibility, biodegradability, and ease of functionalization. One of the significant challenges in treating neurological conditions is overcoming the blood-brain barrier (BBB), which restricts the effective delivery of therapeutic agents to the brain. Addressing this barrier is crucial for the successful treatment of various neurological diseases, including Alzheimer's disease, Parkinson's disease, epilepsy, migraine, psychotic disorders, and brain tumors. Chitosan nanoparticles offer several advantages: they enhance drug absorption, protect drugs from degradation, and enable targeted delivery. These properties open new possibilities for non-invasive therapies for neurological conditions. Numerous studies have highlighted the neuroprotective potential of chitosan nanoparticles, demonstrating improved outcomes in animal models of neurodegeneration and neuroinflammation. Additionally, surface modifications of these nanoparticles allow for the attachment of specific ligands or molecules, enhancing the precision of drug delivery to neuronal cells. Despite these advancements, several challenges persist in the clinical translation of chitosan nanoparticles. Issues such as large-scale production, regulatory hurdles, and the need for further research into long-term safety must be addressed. This review explores recent advancements in the use of chitosan nanoparticles for managing neurological disorders and outlines potential future directions in this rapidly evolving field of research.