Role In Pathogenesis Of Parkinson's Disease Research Articles

Orientin Modulates Nrf2-ARE, PI3K/Akt, JNK-ERK1/2, and TLR4/NF-kB Pathways to Produce Neuroprotective Benefits in Parkinson's Disease.

Parkinson's disease (PD) is characterized by oxidative stress and neuroinflammation as key pathological features. Emerging evidence suggests that nuclear factor erythroid 2 related factor 2-antioxidant response element (Nrf2-ARE), phosphatidylinositol 3‑kinase-protein kinase B (PI3K-Akt), c-Jun N-terminal kinase-extracellular signal-regulated kinase 1/2 (JNK-ERK1/2), and toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kB) pathways play pivotal roles in PD pathogenesis. Orientin, a phenolic phytoconstituent, has demonstrated modulatory potential on these pathways in various experimental conditions other than PD. In this study, we aimed to evaluate the neuroprotective effects of Orientin against rotenone-induced neurodegeneration in SH-SY5Y cell lines and the Swiss albino mice model of PD. Orientin was administered at doses 10 and 20µM in cell lines and 10 and 20mg/kg in mice, and its effects on rotenone-induced neurodegeneration were investigated. Oxidative stress markers including mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as inflammatory markers including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured. The expression levels of genes related to Nrf2-ARE (Nrf2), PI3K/Akt (Akt), JNK-ERK1/2 (TNF-α), and TLR4/NF-kB (TNF-α) pathways were measured to understand the modulatory effect of Orientin on these pathways. Additionally, behavioral studies assessing locomotor activity, muscle coordination, and muscle rigidity were conducted with mice. Our results indicate that Orientin dose-dependently attenuated rotenone-induced changes in oxidative stress markers, inflammatory markers, gene expression levels, and behavioral parameters. Therefore, our study concludes that Orientin exhibits significant neuroprotective benefits against rotenone-induced PD by modulating Nrf2-ARE, PI3K-Akt, JNK-ERK1/2, and TLR4/NF-kB pathways.

INVESTIGATION OF GENE EXPRESSION LEVELS OF SOME PROTEINS RELATED TO THE PATHOGENESIS OF PARKINSON'S DISEASE IN RATS EXPOSED TO PRENATAL STRESS

INVESTIGATION OF GENE EXPRESSION LEVELS OF SOME PROTEINS RELATED TO THE PATHOGENESIS OF PARKINSON’S DISEASE IN RATS EXPOSED TO PRENATAL STRESS Ilayda VAROL1*, Sinem Ezgi TURUNC OZOGLU2 1 Department of Biochemistry, Faculty of Pharmacy, Izmir Katip Çelebi University, Izmir, Türkiye 2 Department of Biochemistry, Faculty of Pharmacy, Izmir Katip Çelebi University, Izmir, Türkiye ORCID Numbers: İlayda Varol: 0009-0000-4037-8612 Sinem Ezgi Turunc Ozoglu: 0000-0002-7587-7443 *Corresponding author: Ilayda VAROL Department of Biochemistry, Faculty of Pharmacy, Izmir Katip Çelebi University, Izmir, Türkiye E-mail: varolilayda@gmail.com Tel: +90 507 333 18 35 Ethical Committee Approval: The Ege University Ethics Committee on Animal Experiments approved this study (05/24/2017; Reference No. 2017-023). INVESTIGATION OF GENE EXPRESSION LEVELS OF SOME PROTEINS RELATED TO THE PATHOGENESIS OF PARKINSON’S DISEASE IN RATS EXPOSED TO PRENATAL STRESS Abstract This study was carried out in order to better understand how prenatal stress (PS) may affect the future onset of Parkinson's disease (PD). A dexamethasone-induced PS model was established in rats for the study. Changes in the expression levels of tyrosine hydroxylase (TH), α-synuclein (SNCA), dopamine transporter (SLC6A3), and parkin (PRKN) proteins, which play role in PD pathogenesis, were demonstrated by real-time PCR in the cerebral cortex of male rats exposed to PS. From GD 14 to 21, pregnant rats were injected daily with Dex or saline (100 μg/kg and 1 ml/kg). 3 months after birth, male rats underwent decapitation (n=5), cerebral cortex dissection was performed. Total RNA was isolated from cortexes and used for cDNA synthesis. Gene expression analyzes were performed according to the ∆∆CT method. The statistical differences between groups were analyzed by the Mann-Whitney test. Statistics were deemed significant at a level of 0.05. Dex exposure throughout pregnancy significantly increased mRNA levels of TH and SLC6A3. No significant differences were found in the mRNA levels of PRKN and SNCA between experimental groups. In conclusion, offspring exposed to PS may be more susceptible to PD in adulthood through changes in the cortical mRNA levels of TH and SLC6A3. Keywords: Prenatal stress, Parkinson’s Disease, Tyrosine hydroxylase, Dopamine transporter

Orally administered neohesperidin attenuates MPTP-induced neurodegeneration by inhibiting inflammatory responses and regulating intestinal flora in mice.

Parkinson's disease (PD), a neurodegenerative disease, is the leading cause of movement disorders. Neuroinflammation plays a critical role in PD pathogenesis. Neohesperidin (Neo), a natural flavonoid extracted from citric fruits exhibits anti-inflammatory effects. However, the effect of Neo on PD progression is unclear. This study aimed to investigate the effects of Neo on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice and its underlying mechanism. Our results indicated that Neo administration ameliorated motor impairment and neural damage in MPTP-injected mice, by inhibiting neuroinflammation and regulating gut microbial imbalance. Additionally, Neo administration reduced colonic inflammation and tissue damage. Mechanistic studies revealed that Neo suppressed the MPTP-induced inflammatory response by inhibiting excessive activation of NF-κB and MAPK pathways. In summary, the present study demonstrated that Neo administration attenuates neurodegeneration in MPTP-injected mice by inhibiting inflammatory responses and regulating the gut microbial composition. This study may provide the scientific basis for the use of Neo in the treatment of PD and other related diseases.

Longitudinal dysregulation of long non-coding RNAs in Parkinson's disease.

Long non-coding RNAs (lncRNAs) have been suggested as potential biomarkers for Parkinson's disease (PD). This study aimed to identify blood-based lncRNA transcripts that are dysregulated in PD over time and could serve as peripheral biomarkers. Using RNA-sequencing data from the Parkinson's Progression Markers Initiative, differential expression between case and control groups at five different time points was detected, and pathway analysis was conducted. Seven transcripts, not previously linked to PD, were consistently dysregulated across all time points, while PD-linked lncRNAs were dysregulated at some but not all time points. Pathway analysis highlighted pathways, known to be affected in PD. This suggested that dysregulated lncRNA transcripts could play a role in PD pathogenesis by affecting well-known PD pathways and highlighted their potential as longitudinal biomarkers for PD. Further studies are needed to validate these findings and explore the potential use of identified lncRNAs as diagnostic and therapeutic targets.

Linking Heat Shock Protein 70 and Parkin in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disease that affects millions of elderly people worldwide and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The precise mechanisms underlying the pathogenesis of PD are still not fully understood, but it is well accepted that the misfolding, aggregation, and abnormal degradation of proteins are the key causative factors of PD. Heat shock protein 70 (Hsp70) is a molecular chaperone that participates in the degradation of misfolded and aggregated proteins in living cells and organisms. Parkin, an E3 ubiquitin ligase, participates in the degradation of proteins via the proteasome pathway. Recent studies have indicated that both Hsp70 and Parkin play pivotal roles in PD pathogenesis. In this review, we focus on discussing how dysregulation of Hsp70 and Parkin leads to PD pathogenesis, the interaction between Hsp70 and Parkin in the context of PD and their therapeutic applications in PD.

Potential direct role of synuclein in dopamine transport and its implications for Parkinson's disease pathogenesis

Parkinson Disease (PD) is a progressive neurodegenerative disorder that is caused by dysfunction and death of dopaminergic neurons. Mutations in the gene encoding α-synuclein (ASYN) have been linked with familial PD (FPD). Despite important role of ASYN in PD pathology, its normal biological function has not been clarified, although direct action of ASYN in synaptic transmission and dopamine (DA+) release have been proposed. In the present report we propose a novel hypothesis that ASYN functions as DA+/H+ exchanger that can facilitate transport of dopamine across synaptic vesicle (SV) membrane by taking advantage of proton gradient between SV lumen and cytoplasm. According to this hypothesis, normal physiological role of ASYN consists of fine-tuning levels of dopamine in the SVs based on cytosolic concentration of dopamine and intraluminal pH. This hypothesis is based on similarity in domain structure of ASYN and pHILP, a designed peptide developed to mediate loading of lipid nanoparticles with the cargo molecules. We reason that carboxy-terminal acidic loop D2b domain in both ASYN and pHILP binds cargo molecules. By mimicking DA+ association with E/D residues in D2b domain of ASYN using Tyrosine replacement approach (TR) we have been able to estimate that ASYN is able to transfer 8–12 molecules of dopamine across SV membrane on each DA+/H+ exchange cycle. Our results suggest that familial PD mutations (A30P, E46K, H50Q, G51D, A53T and A53E) will interfere with different steps of the exchange cycle, resulting in partial loss of dopamine transport function phenotype. We also predict that similar impairment in ASYN DA+/H+ exchange function also occurs as a result on neuronal aging due to changes in SV lipid composition and size and also dissipation of pH gradient across SV membrane. Proposed novel functional role of ASYN provides novel insights into its biological role and its role in PD pathogenesis.

Parkinson’s Disease, Parkinsonisms, and Mitochondria: the Role of Nuclear and Mitochondrial DNA

Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in Parkinson's disease (PD) pathophysiology. This paper aims to review the latest literature published, focusing on genetic defects and expression alterations affecting mitochondria-associated genes, in support of their key role in PD pathogenesis. Thanks to the use of new omics approaches, a growing number of studies are discovering alterations affecting genes with mitochondrial functions in patients with PD and parkinsonisms. These genetic alterations include pathogenic single-nucleotide variants, polymorphisms acting as risk factors, and transcriptome modifications, affecting both nuclear and mitochondrial genes. We will focus on alterations of mitochondria-associated genes described by studies conducted on patients or on animal/cellular models of PD or parkinsonisms. We will comment how these findings can be taken into consideration for improving the diagnostic procedures or for deepening our knowledge on the role of mitochondrial dysfunctions in PD.

Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 μM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1β, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg-1·d-1, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

Pharmacological Intervention Targeting FAF1 Restores Autophagic Flux for α-Synuclein Degradation in the Brain of a Parkinson's Disease Mouse Model.

α-Synuclein accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Previously, we reported that Fas-associated factor 1 (FAF1), which plays a role in PD pathogenesis, potentiates α-synuclein accumulation through autophagy impairment in dopaminergic neurons. In this study, we show that KM-819, a FAF1-targeting compound, which has completed phase I clinical trials, interferes with α-synuclein accumulation in the mouse brain, as well as in human neuronal cells (SH-SY5Ys). KM-819 suppressed the accumulation of monomeric, oligomeric, and aggregated forms of α-synuclein in neuronal cells. Furthermore, KM-819 restored the turnover rate of α-synuclein in FAF1-overexpressing SH-SY5Y cells, implicating KM-819-mediated reconstitution of the α-synuclein degradative pathway. In addition, KM-819 reconstituted autophagic flux in FAF1-transfected SH-SY5Y cells, also suppressing α-synuclein-induced mitochondrial dysfunction. Moreover, oral administration of KM-819 also interfered with α-synuclein accumulation in the midbrain of mice overexpressing FAF1 via an adeno-associated virus system. Consistently, KM-819 reduced α-synuclein accumulation in both the hippocampus and the midbrain of human A53T α-synuclein transgenic mice. Collectively, these data imply that KM-819 may have therapeutic potential for patients with PD.

Modulation of miR-181 influences dopaminergic neuronal degeneration in a mouse model of Parkinson’s disease

Parkinson's disease (PD) is caused by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although PD pathogenesis is not fully understood, studies implicate perturbations in gene regulation, mitochondrial function, and neuronal activity. MicroRNAs (miRs) are small gene regulatory RNAs that inhibit diverse subsets of target mRNAs, and several studies have noted miR expression alterations in PD brains. For example, miR-181a is abundant in the brain and is increased in PD patient brain samples; however, the disease relevance of this remains unclear. Here, we show that miR-181 target mRNAs are broadly downregulated in aging and PD brains. To address whether the miR-181 family plays a role in PD pathogenesis, we generated adeno-associated viruses (AAVs) to overexpress and inhibit the miR-181 isoforms. After co-injection with AAV overexpressing alpha-synuclein (aSyn) into mouse SN (PD model), we found that moderate miR-181a/b overexpression exacerbated aSyn-induced DA neuronal loss, whereas miR-181 inhibition was neuroprotective relative to controls (GFP alone and/or scrambled RNA). Also, prolonged miR-181 overexpression in SN alone elicited measurable neurotoxicity that is coincident with an increased immune response. mRNA-seq analyses revealed that miR-181a/b inhibits genes involved in synaptic transmission, neurite outgrowth, and mitochondrial respiration, along with several genes having known protective roles and genetic links in PD.

Neuroprotective effects of curcumin on the cerebellum in a rotenone-induced Parkinson's Disease Model.

AimsParkinson's disease (PD) is the second most prevalent age‐related neurodegenerative disorder. The cerebellum plays a role in PD pathogenesis. Curcumin has numerous medicinal uses, mostly attributed to its potent antioxidant properties. This study investigated the potential protective influence of curcumin on the cerebellum of albino rats with rotenone‐induced PD.MethodsForty adult male albino rats were randomized into four treatment groups: vehicle (group I); rotenone 3 mg/kg/day i.p. injection (group II); rotenone 3 mg/kg/day plus curcumin 30 mg/kg/day i.p. injection (group III); and curcumin 30 mg/kg/day i.p. injection (group IV).ResultsCompared to group I, group II exhibited marked degenerative changes in hematoxylin & eosin‐stained sections and a reduction in Nissl granules in the Purkinje cells of the cerebellum. In group III, the neurotoxic effects in the cerebellum were reduced. Furthermore, the degenerated Purkinje and GFAP‐positive cells increased considerably in group II and were partially reduced in group III versus group II. Compared to group I, rats in group II showed reduced rotarod motor activity, partially restored in group III. Acetylcholine esterase, glutathione, and superoxide dismutase were significantly reduced, and malondialdehyde was significantly increased in group II compared to group I and was partially increased in group III.ConclusionCurcumin attenuated neurotoxic effects and degenerative histological changes and alleviated induced oxidative stress in the cerebellar cortex of a PD rat model. Therefore, curcumin dietary supplementation may have neuroprotective effects against the development of cerebellum‐related PD symptoms.

Immunotherapeutic interventions in Parkinson's disease: Focus on α-Synuclein.

Parkinson's disease (PD) is a neurodegenerative disorder characterized classically by motor manifestations. However, nonmotor symptoms appear early in the course of the disease progression, making both diagnosis and treatment difficult. The pathology of PD is complicated by the accumulation and aggregation of misfolded proteins in intracellular cytoplasmic inclusions called Lewy bodies (LBs). The main toxic component of LBs is the protein α-Synuclein which plays a pivotal role in PD pathogenesis. α-Synuclein can propagate from cell-to-cell exhibiting prion-like properties and spread PD pathology throughout the central nervous system. Immunotherapeutic interventions in PD, both active and passive immunization, have targeted α-Synuclein in both experimental models and clinical trials. In addition, targeting the hyperactive inflammation in PD also holds promise in designing potential immunotherapeutics. The inflammatory and proteotoxic pathways are interlinked and contribute immensely to the disease pathology. In this chapter, we critically review the targets of immunotherapeutic interventions in PD, focusing on the pathogenetic mechanisms of PD, particularly neuroinflammation and α-Synuclein misfolding, aggregation, and propagation. We thoroughly summarized the various immunotherapeutic strategies designed to treat PD-in vitro, in vivo, and clinical trials. The development of these targeted immunotherapies could open a new avenue in the treatment of patients with PD.

Alpha-synuclein as a biomarker in Parkinson's disease: focus on neural derived extracelluar vesicles.

Alpha-synuclein as a biomarker in Parkinson's disease: focus on neural derived extracelluar vesicles.

Proteome-Wide Profiling of Cellular Targets Modified by Dopamine Metabolites Using a Bio-Orthogonally Functionalized Catecholamine.

Selective death of midbrain dopaminergic neurons is a hallmark pathology of Parkinson's disease (PD), but the molecular mechanisms that initiate the cascade of events resulting in neurodegeneration in PD remain unclear. Compelling evidence suggests that dysregulation of dopamine (DA) induces neuronal stress and damage responses that are operative processes in striatal degeneration preceding PD-like symptoms. Improper DA sequestration to vesicles raises cytosolic DA levels, which is rapidly converted into electrophilic dopaquinone species (DQs) that react readily with protein nucleophiles forming covalent modifications that alter the native structure and function of proteins. These so-called DA-protein adducts (DPAs) have been reported to play a role in neurotoxicity, and their abundance with respect to neurodegeneration has been linked to clinical and pathological features of PD that suggest that they play a causal role in PD pathogenesis. Therefore, characterizing DPAs is a critical first step in understanding the susceptibility of midbrain dopaminergic neurons during PD. To help achieve this goal, we report here a novel DA-mimetic (DAyne) containing a biorthogonal alkyne handle that exhibits a reactivity profile similar to DA in aqueous buffers. By linking DPAs formed with DAyne to a fluorescent reporter molecule, DPAs were visualized in fixed cells and within lysates. DAyne enabled global mapping of cellular proteins affected by DQ modification and their bioactive pathways through enrichment. Our proteomic profiling of DPAs in neuronal SH-SY5Y cells indicates that proteins susceptible to DPA formation are extant throughout the proteome, potentially influencing several diverse biological pathways involved in PD such as endoplasmic reticulum (ER) stress, cytoskeletal instability, proteotoxicity, and clathrin function. We validated that a protein involved in the ER stress pathway, protein disulfide isomerase 3 (PDIA3), which was enriched in our chemoproteomic analysis, is functionally inhibited by DA, providing evidence that dysregulated cellular DA may induce or exacerbate ER stress. Thus, DAyne provided new mechanistic insights into DA toxicity that may be observed during PD by enabling characterization of DPAs generated reproducibly at physiologically relevant quinone exposures. We anticipate our design and application of this reactivity-based probe will be generally applicable for clarifying mechanisms of metabolic quinone toxicity.

Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes.

The glucocerebrosidase 1gene (GBA1), bi-allelic variants of which cause Gaucher disease (GD), encodes the lysosomal enzyme glucocerebrosidase (GCase) and is a risk factor for Parkinson Disease (PD). GBA1 variants are linked to a reduction in GCase activity in the brain. Variants in Leucine-Rich Repeat Kinase 2 (LRRK2), such as the gain-of-kinase-function variant G2019S, cause the most common familial form of PD. In patients without GBA1 and LRRK2 mutations, GCase and LRRK2 activity are also altered, suggesting that these two genes are implicated in all forms of PD and that they may play a broader role in PD pathogenesis. In this review, we review the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway. In particular, we highlight the discovery of Ras-related in brain (Rab) guanosine triphosphatases (GTPases) as LRRK2 kinase substrates and explore the links between increased LRRK2 activity and Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation and GCase activity. We also discuss the discovery of RAB10 as a potential mediator of LRRK2 and GBA1 interaction in PD. Finally, we discuss the therapeutic implications of these findings, including current approaches and future perspectives related to novel drugs targeting LRRK2 and GBA1.

Berberine Attenuates MPP+-Induced Neuronal Injury by Regulating LINC00943/miR-142-5p/KPNA4/NF-κB Pathway in SK-N-SH Cells.

Berberine plays a neuro-protective role in neurodegenerative diseases, including Parkinson's disease (PD). Long non-coding RNAs (lncRNAs) play critical roles in PD pathogenesis. The purpose of this study was to investigate whether LINC00943 was involved in the role of berberine in PD. 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) or 1-methyl-4-phenyl pyridine (MPP+) were used to construct PD mouse and cell models, respectively. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (Edu) assays. Inflammation and cell apoptosis were assessed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. Quantitative real-time PCR (qRT-PCR) was employed to test the expression of LINC00943, microRNA (miR)-142-5p, and karyopherin subunit alpha 4 (KPNA4) mRNA. The protein levels of NF-κB pathway-related markers and KPNA4 were measured by western blot. Oxidative stress level was assessed by corresponding kits. The interaction between miR-142-5p and LINC00943 or KPNA4 was determined via dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Berberine inhibited MPP+-induced injury in SK-N-SH cells by promoting cell proliferation and suppressing inflammation, apoptosis, and oxidative injury. LINC00943 and KPNA4 were upregulated and miR-142-5p was downregulated in PD mouse and cell models. LINC00943 (or KPNA4) overexpression or miR-142-5p inhibition abated the neuro-protective role of berberine in PD cell model. Moreover, miR-142-5p was a target of LINC00943, and KPNA4 could specially bind to miR-142-5p. Additionally, berberine inhibited NF-κB pathway by regulating LINC00943/miR-142-5p/KPNA4 axis. Berberine protected SK-N-SH cell from MPP+-induced neuronal damage via regulating LINC00943/miR-142-5p/KPNA4/NF-κB pathway, highlighting novel evidence for the neuro-protective role of berberine in PD.

Recent Progress in Non-motor Features of Parkinson's Disease with a Focus on Circadian Rhythm Dysregulation.

Parkinson's disease (PD) is the second most common neurodegenerative disease, which manifests with both motor and non-motor symptoms. Circadian rhythm dysregulation, as one of the most challenging non-motor features of PD, usually appears long before obvious motor symptoms. Moreover, the dysregulated circadian rhythm has recently been reported to play pivotal roles in PD pathogenesis, and it has emerged as a hot topic in PD research. In this review, we briefly introduce the circadian rhythm and circadian rhythm-related genes, and then summarize recent research progress on the altered circadian rhythm in PD, ranging from clinical features to the possible causes of PD-related circadian disorders. We believe that future comprehensive studies on the topic may not only help us to explore the mechanisms of PD, but also shed light on the better management of PD.

Impact of the apelin/APJ axis in the pathogenesis of Parkinson's disease with therapeutic potential.

The pathogenesis of Parkinson's disease (PD) remains elusive. There is still no available disease-modifying strategy against PD, whose management is mainly symptomatic. A growing amount of preclinical evidence shows that a complex interplay between autophagy dysregulation, mitochondrial impairment, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation underlies PD pathogenesis. Identifying key molecules linking these pathological cellular processes may substantially aid in our deeper understanding of PD pathophysiology and the development of novel effective therapeutic approaches. Emerging preclinical evidence indicates that apelin, an endogenous neuropeptide acting as a ligand of the orphan G protein-coupled receptor APJ, may play a key neuroprotective role in PD pathogenesis, via inhibition of apoptosis and dopaminergic neuronal loss, autophagy enhancement, antioxidant effects, endoplasmic reticulum stress suppression, as well as prevention of synaptic dysregulation in the striatum, excessive neuroinflammation, and glutamate-induced excitotoxicity. Underlying signaling pathways involve phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin, extracellular signal-regulated kinase 1/2, and inositol requiring kinase 1α/XBP1/C/EBP homologous protein. Herein, we discuss the role of apelin/APJ axis and associated molecular mechanisms on the pathogenesis of PD in vitro and in vivo and provide evidence for its challenging therapeutic potential.

Effects of α-Synuclein-Associated Post-Translational Modifications in Parkinson's Disease.

α-Synuclein (α-syn), a small highly conserved presynaptic protein containing 140 amino acids, is thought to be the main pathological hallmark in related neurodegenerative disorders. Although the normal function of α-syn is closely involved in the regulation of vesicular neurotransmission in these diseases, the underlying mechanisms of post-translational modifications (PTMs) of α-syn in the pathogenesis of Parkinson's disease (PD) have not been fully characterized. The pathological accumulation of misfolded α-syn has a critical role in PD pathogenesis. Recent studies of factors contributing to α-syn-associated aggregation and misfolding have expanded our understanding of the PD disease process. In this Review, we summarize the structure and physiological function of α-syn, and we further highlight the major PTMs (namely phosphorylation, ubiquitination, nitration, acetylation, truncation, SUMOylation, and O-GlcNAcylation) of α-syn and the effects of these modifications on α-syn aggregation, which may elucidate mechanisms for PD pathogenesis and lay a theoretical foundation for clinical treatment of PD.

The Gut-Brain Axis: Two Ways Signaling in Parkinson's Disease.

Parkinson's disease (PD) is a chronic, progressive and second most prevalent neurological disorder affecting the motor system. Cardinal motor impairment and α-synucleinopathy are the characteristic features of PD. Recently, it has been identified that the gut-brain axis is substantially regulated by the gut microbiome (GM) through an immunological, neuroendocrine, and neural mechanism. However, disturbance in the gut-microbiome-brain axis in PD might proceed to gastrointestinal manifestations intermittently leading to the motor system and the PD pathogenesis itself. The gut microbial toxins may induce the production of α-synuclein (α-syn) aggregates in the enteric nervous system (ENS), which may proliferate and propagate in a prion-like-manner through the vagus nerve to the central nervous system (CNS); supporting the hypothesis that, GM might play a pivotal role in PD pathogenesis. Overstimulated innate immune system due to intestinal bacterial overgrowth or gut dysbiosis and the enhanced intestinal permeability may persuade systemic inflammation, while the activation of enteric glial cells and enteric neurons may contribute to α-synucleinopathy. Gut microbiota can bear a significant impact on neurological outcomes such as learning, memory and cognition. In this review paper, we summarize how the alterations in gut microbiota and ENS inflammation are associated with PD pathogenesis. The evidence supporting the causative role played by gut-associated dysbiosis and microbial byproducts, in the onset of PD is also discussed. We have highlighted the landmark discoveries in the field of PD particularly focusing on the gut-brain axis. A better comprehension of the interaction between the gut-brain axis, gut microbiota, and PD can usher in novel therapeutic and diagnostic approaches.