Pathogenesis Of Parkinson's Disease Research Articles

The immune system in Parkinson's disease: what we know so far.

Parkinson's disease (PD) is characterised neuropathologically by the degeneration of dopaminergic neurons in the ventral midbrain, the accumulation of α-synuclein (α-syn) aggregates in neurons, and chronic neuroinflammation. In the past two decades, in vitro, ex vivo and in vivo studies have consistently shown the involvement of inflammatory responses mediated by microglia and astrocytes, which may be elicited by pathological α-syn or signals from affected neurons and other cell types, and are directly linked to neurodegeneration and disease development. Besides the prominent immune alterations seen in the central nervous system (CNS), including the infiltration of T-cells into the brain, more recent studies have demonstrated important changes in the peripheral immune profile within both the innate and adaptive compartments, particularly involving monocytes, CD4+ and CD8+ T-cells. This review aims to integrate the consolidated understanding of immune-related processes underlying the pathogenesis of PD, focusing on both central and peripheral immune cells, neuron-glia crosstalk as well as the central-peripheral immune interaction during the development of PD. Our analysis seeks to provide a comprehensive view of the emerging knowledge of the mechanisms of immunity in PD and the implications of this for better understanding the overall pathogenesis of this disease.

Cyclin-dependent kinase 5 (CDK5) inhibitors in Parkinson disease.

Cyclin-dependent kinase 5 (Cdk5) is a protein expressed in postmitotic neurons in the central nervous system (CNS). Cdk5 is activated by p35 and p39 which are neuron regulatory subunits. Cdk5/p35 complex is activated by calpain protease to form Cdk5/p35 which has a neuroprotective effect by regulating the synaptic plasticity and memory functions. However, exaggerated Cdk5 is implicated in different types of neurodegenerative diseases including Parkinson disease (PD). Therefore, modulation of Cdk5 signalling may mitigate PD neuropathology. Therefore, the aim of the present review was to discuss the critical role of Cdk5 in the pathogenesis of PD, and how Cdk5 inhibitors are effectual in the management of PD. In conclusion, overactivated Cdk5 is involved the development of neurodegeneration, and Cdk5/calpain inhibitors such as statins, metformin, fenofibrates and rosiglitazone can attenuate the progression of PD neuropathology.

Epidemiology of Parkinson's Disease: An Update.

In recent decades, epidemiological understanding of Parkinson disease (PD) has evolved significantly. Major discoveries in genetics and large epidemiological investigations have provided a better understanding of the genetic, behavioral, and environmental factors that play a role in the pathogenesis and progression of PD. In this review, we provide an epidemiological update of PD with a particular focus on advances in the last five years of published literature. We include an overview of PD pathophysiology, followed by a detailed discussion of the known distribution of disease and varied determinants of disease. We describe investigations of risk factors for PD, and provide a critical summary of current knowledge, knowledge gaps, and both clinical and research implications. We emphasize the need to characterize the epidemiology of the disease in diverse populations. Despite increasing understanding of PD epidemiology, recent paradigm shifts in the conceptualization of PD as a biological entity will also impact epidemiological research moving forward and guide further work in this field.

Quantitative susceptibility mapping of multiple system atrophy and Parkinson's disease correlates with neurotransmitter reference maps

BackgroundMultiple system atrophy (MSA) and Parkinson's disease (PD) are neurodegenerative disorders characterized by α-synuclein pathology, disrupted iron homeostasis and impaired neurochemical transmission. Considering the critical role of iron in neurotransmitter synthesis and transport, our study aims to identify distinct patterns of whole-brain iron accumulation in MSA and PD, and to elucidate the corresponding neurochemical substrates. MethodsA total of 122 PD patients, 58 MSA patients and 78 age-, sex-matched health controls underwent multi-echo gradient echo sequences and neurological evaluations. We conducted voxel-wise and regional analyses using quantitative susceptibility mapping to explore MSA or PD-specific alterations in cortical and subcortical iron concentrations. Spatial correlation approaches were employed to examine the topographical alignment of cortical iron accumulation patterns with normative atlases of neurotransmitter receptor and transporter densities. Furthermore, we assessed the associations between the colocalization strength of neurochemical systems and disease severity. ResultsMSA patients exhibited increased susceptibility in the striatal, midbrain, cerebellar nuclei, as well as the frontal, temporal, occipital lobes, and anterior cingulate gyrus. In contrast, PD patients displayed elevated iron levels in the left inferior occipital gyrus, precentral gyrus, and substantia nigra. The excessive iron accumulation in MSA or PD correlated with the spatial distribution of cholinergic, noradrenaline, glutamate, serotonin, cannabinoids, and opioid neurotransmitters, and the degree of this alignment was related to motor deficits. ConclusionsOur findings provide evidence of the interaction between iron accumulation and non-dopamine neurotransmitters in the pathogenesis of MSA and PD, which inspires research on potential targets for pharmacotherapy.

Effects of bound nucleotides on the secondary structure, thermal stability, and phosphorylation of Rab3A

Rab3A is a member of the Rab GTPase family involved in synaptic vesicle trafficking. Recent evidence has demonstrated that Rab3A is phosphorylated by leucine-rich repeat kinase 2 (LRRK2) that is implicated in both familial and sporadic forms of Parkinson's disease (PD), and an abnormal increase in Rab3A phosphorylation has been proposed as a cause of PD. Despite the potential importance of Rab3A in PD pathogenesis, its structural information is limited and the effects of bound nucleotides on its biophysical and biochemical properties remain unclear. Here, we show that GDP-bound Rab3A is preferentially phosphorylated by LRRK2 compared with GTP-bound Rab3A. The secondary structure of Rab3A, measured by circular dichroism (CD) spectroscopy, revealed that Rab3A is resistant to heat-induced denaturation at pH 7.4 or 9.0 regardless of the nucleotides bound. In contrast, Rab3A underwent heat-induced denaturation at pH 5.0 at a lower temperature in its GDP-bound form than in its GTP-bound form. The unfolding temperature of Rab3A was studied by differential scanning fluorimetry, which showed a significantly higher unfolding temperature in GTP-bound Rab3A than in GDP-bound Rab3A, with the highest at pH 7.4. These results suggest that Rab3A has unusual thermal stability under physiologically relevant conditions and that bound nucleotides influence both thermal stability and phosphorylation by LRRK2.

The mechanisms of white matter injury and immune system crosstalk in promoting the progression of Parkinson's disease: a narrative review.

Parkinson's disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood-brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood-brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.

Bidirectional communication of the gut-brain axis: new findings in Parkinson’s disease and inflammatory bowel disease

Parkinson’s disease (PD) and inflammatory bowel disease (IBD) are the two chronic inflammatory diseases that are increasingly affecting millions of people worldwide, posing a major challenge to public health. PD and IBD show similarities in epidemiology, genetics, immune response, and gut microbiota. Here, we review the pathophysiology of these two diseases, including genetic factors, immune system imbalance, changes in gut microbial composition, and the effects of microbial metabolites (especially short-chain fatty acids). We elaborate on the gut–brain axis, focusing on role of gut microbiota in the pathogenesis of PD and IBD. In addition, we discuss several therapeutic strategies, including drug therapy, fecal microbiota transplantation, and probiotic supplementation, and their potential benefits in regulating intestinal microecology and relieving disease symptoms. Our analysis will provide a new understanding and scientific basis for the development of more effective therapeutic strategies for these diseases.

EEF1A1 regulates the expression and alternative splicing of genes associated with Parkinson's disease in U251 cells.

Eukaryotic elongation factor 1A1 (eEF1A1) is an RNA-binding protein that is associated with PARK2 activity in cells, suggesting a possible role in Parkinson's disease (PD). To clear whether eEF1A1 plays a role in PD through transcriptional or posttranscriptional regulation. The GSE68719 dataset was downloaded from the GEO database, and the RNA-seq data of all brain tissue autopsies were obtained from 29 PD patients and 44 neurologically normal control subjects. To inhibit eEF1A1 from being expressed in U251 cells, siRNA was transfected into those cells, and RNA-seq high-throughput sequencing was used to determine the differentially expressed genes (DEGs) and differentially alternative splicing events (ASEs) resulting from eEF1A1 knockdown. eEF1A1 was significantly overexpressed in PD brain tissue in the BA9 area. GO and KEGG enrichment analyses revealed that eEF1A1 knockdown significantly upregulated the expression of the genes CXCL10, NGF, PTX3, IL6, ST6GALNAC3, NUPR1, TNFRSF21, and CXCL2 and upregulated the alternative splicing of the genes ACOT7, DDX10, SHMT2, MYEF2, and NDUFAF5. These genes were enriched in pathways related to PD pathogenesis, such as apoptosis, inflammatory response, and mitochondrial dysfunction. The results suggesting that eEF1A1 involved in the development of PD by regulating the differential expression and alternative splicing of genes, providing a theoretical basis for subsequent research.

Understanding the (epi)genetic dysregulation in Parkinson's disease through an integrative brain competitive endogenous RNA network

Parkinson’s disease (PD) is a rapidly growing neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SN) and aggregation of α-synuclein. Its aetiology involves a multifaceted interplay among genetic, environmental, and epigenetic factors. We integrated brain gene expression data from PD patients to construct a comprehensive regulatory network encompassing messenger RNAs (mRNAs), microRNAs (miRNAs), circular RNAs (circRNAs) and, for the first time, RNA binding proteins (RBPs). Expression data from the SN of PD patients and controls were systematically selected from public databases to identify combined differentially expressed genes (DEGs). Brain co-expression analysis revealed modules comprising significant DEGs that function cooperatively. The relationships among co-expressed DEGs, miRNAs, circRNAs, and RBPs revealed an intricate competitive endogenous RNA (ceRNA) network responsible for post-transcriptional dysregulation in PD. Many genes in the ceRNA network, including the TOMM20 and HMGCR genes, overlap with the most relevant genes in our previous Alzheimer’s disease-associated ceRNA network, suggesting common underlying mechanisms between both conditions. Moreover, in the ceRNA subnetwork, the RBP Aly/REF export factor (ALYREF), which acts as an RNA 5-methylcytosine(m5C)-binding protein, stood out. Our data sheds new light on the potential role of brain ceRNA networks in PD pathogenesis.

Harnessing Graphdiyne for Selective Cu2+ Detection: A Promising Tool for Parkinson's Disease Diagnostics and Pathogenesis.

Cu2+ accelerates the viral-like propagation of α-synuclein fibrils and plays a key role in the pathogenesis of Parkinson's disease (PD). Therefore, the accurate detection of Cu2+ is essential for the diagnosis of PD and other neurological diseases. The Cu2+ detection process is impeded by substances that have similar electrochemical properties. In this study, graphdiyne (GDY), a new kind of carbon allotrope with strong electron-donating ability, was utilized for the highly selective detection of Cu2+ by taking advantage of its outstanding adsorption capacity for Cu2+. Density functional theory (DFT) calculations show that Cu atoms are adsorbed in the cavity of GDY, and the absorption energy between Cu and C atoms is higher than that of graphene (GR), indicating that the cavity of GDY is favorable for the adsorption of Cu atoms and electrochemical sensing. The GDY-based electrochemical sensor can effectively avoid the interference of amino acids, metal ions and neurotransmitters and has a high sensitivity of 9.77 μA·μM-1·cm-2, with a minimum detectable concentration of 200 nM. During the investigating pathogenesis and therapeutic process of PD with α-synuclein as the diagnostic standard, the concentration of Cu2+ in cells before and after L-DOPA and GSH treatments were examined, and it was found that Cu2+ exhibits high potential as a biomarker for PD. This study not only harnesses the favorable adsorption of the GDY and Cu2+ to improve the specificity of ion detection but also provide clues for deeper understanding of the role of Cu2+ in neurobiology and neurological diseases.

Paraquat disrupts KIF5A-mediated axonal mitochondrial transport in midbrain neurons and its antagonism by melatonin

Paraquat (PQ) is a broad-spectrum herbicide used worldwide and is a hazardous chemical to human health. Cumulative evidence strengthens the association between PQ exposure and the development of Parkinson's disease (PD). However, the underlying mechanism and effective interventions against PQ-induced neurotoxicity remain unclear. In this study, C57BL/6 J mice were treated with PQ (i.p., 10 mg/kg, twice a week) and melatonin (i.g., 20 mg/kg, twice a week) for 8 weeks. Results showed that PQ-induced motor deficits and midbrain dopaminergic neuronal damage in C57BL/6 J mice were protected by melatonin pretreatment. In isolated primary midbrain neurons and SK-N-SH cells, reduction of cell viability, elevation of total ROS levels, axonal mitochondrial transport defects and mitochondrial dysfunction caused by PQ were attenuated by melatonin. After screening of expression of main motors driving axonal mitochondrial transport, data showed that PQ-decreased KIF5A expression in mice midbrain and in SK-N-SH cell was antagonized by melatonin. Using the in vitro KIF5A-overexpression model, it was found that KIF5A overexpression inhibited PQ-caused neurotoxicity and mitochondrial dysfunction in SK-N-SH cells. In addition, application of MTNR1B (MT2) receptor antagonist, 4-P-PDOT, significantly counteracted the protection of melatonin against PQ-induced neurotoxicity. Further, Kif5a-knockdown diminished melatonin-induced alleviation of motor deficits and neuronal damage against PQ in C57BL/6 J mice. The present study establishes a causal link between environmental neurotoxicants exposure and PD etiology and provides effective interventive targets in the pathogenesis of PD.

Nigrostriatal Inflammation Is Associated with Nonmotor Symptoms in an Experimental Model of Prodromal Parkinson’s Disease

Recent evidence has supported a pathogenic role for neuroinflammation in Parkinson’s disease (PD). Inflammatory response has been associated with symptoms and subtypes of PD. However, it is unclear whether immune changes are involved in the initial pathogenesis of PD, leading to the non-motor symptoms (NMS) observed in its prodromal stage. The current study aimed to characterize the behavioral and cognitive changes in a toxin-induced model of prodromal PD-like syndrome. We also sought to investigate the role of neuroinflammation in prodromal PD-related NMS. Male mice were subjected to bilateral intranasal infusion with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or saline (control group), followed by comprehensive behavioral, pathological and neurochemical analysis. Intranasal MPTP infusion was able to cause the loss of dopaminergic neurons in the substantia nigra (SN). In parallel, it induced impairment in olfactory discrimination and social memory consolidation, compulsive and anxiety-like behaviors, but did not influence motor performance. Iba-1 and GFAP expressions were increased in the SN, suggesting an activated state of microglia and astrocytes. Consistent with this, MPTP mice had increased levels of IL-10 and IL-17A, and decreased levels of BDNF and TrkA mRNA in the SN. The striatum showed increased IL-17A, BDNF, and NFG levels compared to control mice. In conclusion, neuroinflammation may play an important role in the early stage of experimental PD-like syndrome, leading to cognitive and behavioral changes. Our results also indicate that intranasal administration of MPTP may represent a valuable mouse model for prodromal PD.

Integrative analysis of plasma and substantia nigra in Parkinson's disease: unraveling biomarkers and insights from the lncRNA-miRNA-mRNA ceRNA network.

Parkinson's disease (PD) is a rapidly growing neurological disorder characterized by diverse movement symptoms. However, the underlying causes have not been clearly identified, and accurate diagnosis is challenging. This study aimed to identify potential biomarkers suitable for PD diagnosis and present an integrative perspective on the disease. We screened the GSE7621, GSE8397-GPL96, GSE8397-GPL97, GSE20163, and GSE20164 datasets in the NCBI GEO database to identify differentially expressed (DE) mRNAs in the substantia nigra (SN). We also screened the GSE160299 dataset from the NCBI GEO database to identify DE lncRNAs and miRNAs in plasma. We then constructed 2 lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) regulatory networks based on the ceRNA hypothesis. To understand the biological function, we performed Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analyses for each ceRNA network. The receiver operating characteristic analyses (ROC) was used to assess ceRNA results. We identified 7 upregulated and 29 downregulated mRNAs as common DE mRNAs in the 5 SN datasets. In the blood dataset, we identified 31 DE miRNAs (9 upregulated and 22 downregulated) and 332 DE lncRNAs (69 upregulated and 263 downregulated). Based on the determined interactions, 5 genes (P2RX7, HSPA1, SLCO4A1, RAD52, and SIRT4) appeared to be upregulated as a result of 10 lncRNAs sponging 4 miRNAs (miR-411, miR-1193, miR-301b, and miR-514a-2/3). Competing with 9 genes (ANK1, CBLN1, RGS4, SLC6A3, SYNGR3, VSNL1, DDC, KCNJ6, and SV2C) for miR-671, a total of 26 lncRNAs seemed to function as ceRNAs, influencing genes to be downregulated. In this study, we successfully constructed 2 novel ceRNA regulatory networks in patients with PD, including 36 lncRNAs, 5 miRNAs, and 14 mRNAs. Our results suggest that these plasma lncRNAs are involved in the pathogenesis of PD by sponging miRNAs and regulating gene expression in the SN of the brain. We propose that the upregulated and downregulated lncRNA-mediated ceRNA networks represent mechanisms of neuroinflammation and dopamine neurotransmission, respectively. Our ceRNA network, which was associated with PD, suggests the potential use of DE miRNAs and lncRNAs as body fluid diagnostic biomarkers. These findings provide an integrated view of the mechanisms underlying gene regulation and interactions in PD.

Ultrastructural Changes of Neuroendocrine Pheochromocytoma Cell Line PC-12 Exposed In Vitro to Rotenone.

Rotenone is a pesticide used in research for its ability to induce changes similar, in vivo and in vitro, to those observed in Parkinson's disease (PD). This includes a selective death of dopaminergic neurons in the substantia nigra. Nonetheless, the precise mechanism through which rotenone modifies structure and function of neurons remains unclear. The PC12 cells closely resemble dopamine terminal neurons. This makes it a preferred model for studying the morphology of central dopamine neurons and predicting neurotoxicity. In this paper, we investigated the effects of 0.5 µM rotenone for 24-48 h on PC12 cell viability and ultrastructure (TEM), trying to identify primary and more evident alterations that can be related to neuronal damages similar to that seen in animal PD models. Cell viability decreased after 24 h rotenone treatment, with a further decrease after 48 h. Ultrastructural changes included vacuolar degeneration, mitochondrial mild swelling, decrease in the number of neuropeptide granules, and the loss of cell-to-cell adhesion. These findings are in agreement with previous research suggesting that rotenone, by inhibiting energy production and increasing ROS generation, is responsible for significant alterations of the ultrastructure and cell death of PC12 cells. Our data confirm the link between rotenone exposure, neuronal damage, and changes in dopamine metabolism, suggesting its role in the pathogenesis of PD.

A new mutation in the Parkinson's-related FBXO7 gene impairs mitochondrial and proteasomal function.

Around 10% of Parkinson's disease (PD) cases are associated with mutations in various genes, including FBXO7, which encodes the substrate-recognition component for the Skp1-Cullin-F-box (SCF) class of ubiquitin E3 ligases that target proteins for proteasomal degradation. In their recent study, Al Rawi etal. characterized a new mutation in FBXO7, L250P, in a pediatric patient. Their findings reveal that the L250P mutation abolishes Fbxo7 interaction with the proteasome regulator, proteasome inhibitor 31kD (PI31), affecting proteasomal activity and the ubiquitination of some of the ligase's targets. Furthermore, the authors show that this previously undescribed mutation impairs mitochondrial function and mitophagy, emphasizing the importance of mitochondrial and proteasomal dysfunction in PD pathogenesis.

Association Between Neuroinflammation and Parkinson's Disease: A Comprehensive Mendelian Randomization Study.

The objective of the study is to determine the causal relationship and potential mechanisms between Parkinson's disease (PD) and neuroinflammatory and neurotoxic mediators. We conducted two-sample Mendelian randomization (2SMR) study and multivariable Mendelian randomization (MVMR) analysis to investigate the causality between PD and neuroinflammatory and neurotoxic mediators. The mediation analysis with MR was also conducted to determine the potential mediating effect of neuroinflammatory and neurotoxic mediators between asthma and PD. Genetically predicted levels of nine neuroinflammation were associated with changes in PD risk. The associations of PD with CCL24, galectin-3 levels, haptoglobin, and Holo-Transcobalamin-2 remained significant in multivariable analyses. The mediation analysis with MR revealed that asthma affects PD through CCL24 and galectin-3. The results showed neuroinflammation could affect the pathogenesis of PD. In the combined analysis of these nine variables, CCL24, galectin-3 levels, HP, and Holo-Transcobalamin-2 alone were found to be significant. Asthma plays an intermediary role through CCL24 and galectin-3 levels.

The role of age-associated alpha-synuclein aggregation in a conditional transgenic mouse model of Parkinson's disease: Implications for Lewy body formation.

Parkinson's disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α-synuclein (α-syn), a major component of Lewy bodies, which are a classical pathological hallmark of PD. These findings suggest that α-syn is an important contributor to the development of PD. In our previous study, we developed an adenoviral mouse model of PD and showed that the expression of wild-type (WT) α-syn or a mutant form with an increased propensity to aggregate, designated as WT-CL1 α-syn, could be used to study how α-syn aggregation contributes to PD. In this study, we established a transgenic mouse model that conditionally expresses WT or WT-CL1 α-syn in dopaminergic (DA) neurons and found that the expression of either WT or WT-CL1 α-syn was associated with an age-dependent degeneration of DA neurons and movement dysfunction. Using this model, we were able to monitor the process of α-syn aggregate formation and found a correlation between age and the number and sizes of α-syn aggregates formed. These results provide a potential mechanism by which age-dependent α-syn aggregation may lead to the formation of Lewy bodies in PD pathogenesis.

Autophagy-associated non-coding RNAs: Unraveling their impact on Parkinson's disease pathogenesis.

Parkinson's disease (PD) is a degenerative neurological condition marked by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta. The precise etiology of PD remains unclear, but emerging evidence suggests a significant role for disrupted autophagy-a crucial cellular process for maintaining protein and organelle integrity. This review focuses on the role of non-coding RNAs (ncRNAs) in modulating autophagy in PD. We conducted a comprehensive review of recent studies to explore how ncRNAs influence autophagy and contribute to PD pathophysiology. Special attention was given to the examination of ncRNAs' regulatory impacts in various PD models and patient samples. Findings reveal that ncRNAs are pivotal in regulating key processes associated with PD progression, including autophagy, α-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation. Dysregulation of specific ncRNAs appears to be closely linked to these pathogenic processes. ncRNAs hold significant therapeutic potential for addressing autophagy-related mechanisms in PD. The review highlights innovative therapeutic strategies targeting autophagy-related ncRNAs and discusses the challenges and prospective directions for developing ncRNA-based therapies in clinical practice. The insights from this study underline the importance of ncRNAs in the molecular landscape of PD and their potential in novel treatment approaches.

Electroacupuncture blocked motor dysfunction and gut barrier damage by modulating intestinal NLRP3 inflammasome in MPTP-induced Parkinson's disease mice

Parkinson's disease (PD) is a neurodegenerative disorder commonly accompanied by gut dysfunction. EA has shown anti-inflammatory and neuroprotective effects. Here, we aim to explore whether EA can treat Parkinson's disease by restoring the intestinal barrier and modulating NLRP3 inflammasome. We applied 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model and EA at the GV16, LR3, and ST36 for 12 consecutive days. The open-field test results indicated that EA alleviated depression and behavioral defects, upregulated the expressions of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), and blocked the accumulation of α-synuclein (α-syn) in the midbrain. Moreover, EA blocked the damage to intestinal tissues of PD mice, indicative of suppressed NLRP3 inflammasome activation and increased gut barrier integrity. Notably, the antibiotic-treated mouse experiment validated that the gut microbiota was critical in alleviating PD dyskinesia and intestinal inflammation by EA. In conclusion, this study suggested that EA exhibited a protective effect against MPTP-induced PD by alleviating behavioral defects, reversing the block of motor dysfunction, and improving the gut barrier by modulating intestinal NLRP3 inflammasome. Above all, this study could provide novel insights into the pathogenesis and therapy of PD.

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics.

Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson's disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain's microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.