Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease.Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease,appearing in about 90%of patients with early-stage Parkinson’s disease,and can often predate the diagnosis by years.Therefore,olfactory dysfunction should be considered a reliable marker of the disease.However,the mechanisms responsible for olfactory dysfunction are currently unknown.In this article,we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease.On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression levels,we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease.The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease.Therefore,therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms,highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

Effects of mesenchymal stem cell on dopaminergic neurons,motor and memory functions in animal models of Parkinson's disease:a systematic review and meta-analysis

Parkinson’s disease is chara cterized by the loss of dopaminergic neurons in the substantia nigra pars com pacta,and although restoring striatal dopamine levels may improve symptoms,no treatment can cure or reve rse the disease itself.Stem cell therapy has a regenerative effect and is being actively studied as a candidate for the treatment of Parkinson’s disease.Mesenchymal stem cells are considered a promising option due to fewer ethical concerns,a lower risk of immune rejection,and a lower risk of teratogenicity.We performed a meta-analysis to evaluate the therapeutic effects of mesenchymal stem cells and their derivatives on motor function,memory,and preservation of dopamine rgic neurons in a Parkinson’s disease animal model.We searched bibliographic databases(PubMed/MEDLINE,Embase,CENTRAL,Scopus,and Web of Science)to identify articles and included only pee r-reviewed in vivo interve ntional animal studies published in any language through J une 28,2023.The study utilized the random-effect model to estimate the 95%confidence intervals(CI)of the standard mean differences(SMD)between the treatment and control groups.We use the systematic review center for laboratory animal expe rimentation’s risk of bias tool and the collaborative approach to meta-analysis and review of animal studies checklist for study quality assessment.A total of 33studies with data from 840 Parkinson’s disease model animals were included in the meta-analysis.Treatment with mesenchymal stem cells significantly improved motor function as assessed by the amphetamine-induced rotational test.Among the stem cell types,the bone marrow MSCs with neurotrophic factor group showed la rgest effect size(SMD[95%CI]=-6.21[-9.50 to-2.93],P=0.0001,I^(2)=0.0%).The stem cell treatment group had significantly more tyrosine hydroxylase positive dopamine rgic neurons in the striatum([95%CI]=1.04[0.59 to 1.49],P=0.0001,I^(2)=65.1%)and substantia nigra(SMD[95%CI]=1.38[0.89 to 1.87],P=0.0001,I^(2)=75.3%),indicating a protective effect on dopaminergic neurons.Subgroup analysis of the amphetamine-induced rotation test showed a significant reduction only in the intracranial-striatum route(SMD[95%CI]=-2.59[-3.25 to-1.94],P=0.0001,I^(2)=74.4%).The memory test showed significant improvement only in the intravenous route(SMD[95%CI]=4.80[1.84 to 7.76],P=0.027,I^(2)=79.6%).Mesenchymal stem cells have been shown to positively impact motor function and memory function and protect dopaminergic neurons in preclinical models of Parkinson’s disease.Further research is required to determine the optimal stem cell types,modifications,transplanted cell numbe rs,and delivery methods for these protocols.

Cell reprogramming therapy for Parkinson’s disease

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Roles of neuronal lysosomes in the etiology of Parkinson’s disease

Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology.The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease.In this respect,the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics,genomics,and pathologic indications,spanning both familial and idiopathic Parkinson’s disease.Most,if not all,genes linked to familial disease are involved,in a regulatory capacity,in lysosome function(e.g.,LRRK2,alpha-synuclein,VPS35,Parkin,and PINK1).Moreover,the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation(GBA as the prime example).Lastly,neuropathologic evidence showed alterations in lysosome markers in autoptic material that,coupled to the alpha-synuclein proteinopathy that defines the disease,strongly indicate an alteration in functionality.In this Brief Review article,I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis,aiming at a larger vision on the events underlying the onset of the disease.The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at“indiscriminately”enhancing its activity to promote the degradation and elimination of aggregate protein accumulations,such as alpha-synuclein Lewy bodies.However,this approach is based on the assumption that protein pathology is the root cause of disease,while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings.In addition,it has been reported that unspecific boosting of autophagy can be detrimental.Thus,it is important to understand the mechanisms of specific autophagy forms and,even more,the adjustment of specific lysosome functionalities.Indeed,lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions.Here,I discuss hypotheses on these possible mechanisms,their links with etiologic and risk factors for Parkinson’s disease,and how they could be targeted for disease-modifying purposes.

Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders:current knowledge and future directions

Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins,includingα-synuclein,amyloid-β,and tau,in addition to the impaired elimination of these neurotoxic protein.Atypical parkinsonism,which has the same clinical presentation and neuropathology as Parkinson’s disease,expands the disease landscape within the continuum of Parkinson’s disease and related disorders.The glymphatic system is a waste clearance system in the brain,which is responsible for eliminating the neurotoxic proteins from the interstitial fluid.Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease,as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage.Therefore,impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration.Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders;however,many unanswered questions remain.This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders.The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins,including loss of polarization of aquaporin-4 in astrocytic endfeet,sleep and circadian rhythms,neuroinflammation,astrogliosis,and gliosis.This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders,and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy.

Deep brain implantable microelectrode arrays for detection and functional localization of the subthalamic nucleus in rats with Parkinson’s disease

The subthalamic nucleus(STN)is considered the best target for deep brain stimulation treatments of Parkinson’s disease(PD).It is difficult to localize the STN due to its small size and deep location.Multichannel microelectrode arrays(MEAs)can rapidly and precisely locate the STN,which is important for precise stimulation.In this paper,16-channel MEAs modified with multiwalled carbon nanotube/poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate)(MWCNT/PEDOT:PSS)nanocomposites were designed and fabricated,and the accurate and rapid identification of the STN in PD rats was performed using detection sites distributed at different brain depths.These results showed that nuclei in 6-hydroxydopamine hydrobromide(6-OHDA)-lesioned brains discharged more intensely than those in unlesioned brains.In addition,the MEA simultaneously acquired neural signals from both the STN and the upper or lower boundary nuclei of the STN.Moreover,higher values of spike firing rate,spike amplitude,local field potential(LFP)power,and beta oscillations were detected in the STN of the 6-OHDA-lesioned brain,and may therefore be biomarkers of STN localization.Compared with the STNs of unlesioned brains,the power spectral density of spikes and LFPs synchronously decreased in the delta band and increased in the beta band of 6-OHDA-lesioned brains.This may be a cause of sleep and motor disorders associated with PD.Overall,this work describes a new cellular-level localization and detection method and provides a tool for future studies of deep brain nuclei.

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease

Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.

Cath-KP,a novel peptide derived from frog skin,prevents oxidative stress damage in a Parkinson’s disease model

Parkinson’s disease(PD)is a neurodegenerative condition that results in dyskinesia,with oxidative stress playing a pivotal role in its progression.Antioxidant peptides may thus present therapeutic potential for PD.In this study,a novel cathelicidin peptide(Cath-KP;GCSGRFCNLF NNRRPGRLTLIHRPGGDKRTSTGLIYV)was identified from the skin of the Asiatic painted frog(Kaloula pulchra).Structural analysis using circular dichroism and homology modeling revealed a uniqueαββconformation for Cath-KP.In vitro experiments,including free radical scavenging and ferric-reducing antioxidant analyses,confirmed its antioxidant properties.Using the 1-methyl-4-phenylpyridinium ion(MPP^(+))-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced PD mice,Cath-KP was found to penetrate cells and reach deep brain tissues,resulting in improved MPP^(+)-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1(Sirt1)/Nuclear factor erythroid 2-related factor 2(Nrf2)pathway activation.Both focal adhesion kinase(FAK)and p38 were also identified as regulatory elements.In the MPTP-induced PD mice,Cath-KP administration increased the number of tyrosine hydroxylase(TH)-positive neurons,restored TH content,and ameliorated dyskinesia.To the best of our knowledge,this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress.These findings expand the known functions of cathelicidins,and hold promise for the development of therapeutic agents for PD.

Comparative proteomic analysis of plasma exosomes reveals the functional contribution of N-acetyl-alpha-glucosaminidase to Parkinson’s disease

Parkinson’s disease is the second most common progressive neurodegenerative disorder,and few reliable biomarkers are available to track disease progression.The proteins,DNA,mRNA,and lipids carried by exosomes reflect intracellular changes,and thus can serve as biomarkers for a variety of conditions.In this study,we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson’s disease and the potential therapeutic roles of these proteins in Parkinson’s disease.Using a tandem mass tag-based quantitative proteomics approach,we characterized the proteomes of plasma exosomes derived from individual patients,identified exosomal protein signatures specific to patients with Parkinson’s disease,and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein.N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western blot.The results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson’s disease,but also decreased with increasing Hoehn-Yahr stage,suggesting that N-acetyl-alpha-glucosaminidase could be used to rapidly evaluate Parkinson’s disease severity.Furthermore,western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressingα-synuclein compared with control cells.Additionally,N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibitedα-synuclein expression in 1-methyl-4-phenylpyridinium-treated cells.Taken together,our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson’s disease diagnosis,and that N-acetyl-alpha-glucosaminidase may reduceα-synuclein expression and 1-methyl-4-phenylpyridinium-induced neurotoxicity,thus providing a new therapeutic target for Parkinson’s disease.

C-phycocyanin shows neuroprotective effect against rotenone-induced Parkinson’s disease in mice

Objective:To investigate the neuroprotective effect of C-phycocyanin in a mouse model of rotenone-induced Parkinson’s disease.Methods:C-phycocyanin(50 mg/kg,i.p.,daily)was administered to rotenone(30 mg/kg,p.o.,daily)treated mice for 28 days.Behavioral studies(Y-maze,rotarod,round beam walk,and wire-hang tests)were carried out to assess neurobehavioral deficits.Glutathione and malondialdehyde were determined in both serum and striatal tissue.Molecular proteins(AKT,AMPK,NF-κB,BDNF,and alpha-synuclein)in the striatum were estimated using ELISA.Histopathological analyses(hematoxylin and eosin stainning as well as Nissl staining)were carried out to assess structural abnormalities in the striatum.Results:C-phycocyanin significantly increased BDNF levels and decreased alpha-synuclein levels.It also slightly upregulated AMPK and AKT levels without significant difference compared with the rotenone group.Additionally,rotenone-induced elevated oxidative stress and structural abnormalities in the striatum were markedly mitigated by C-phycocyanin.Conclusions:C-phycocyanin might have potential neuroprotective effects against Parkinson’s disease.Further studies are warranted to verify its efficacy and to understand the molecular mechanisms behind the neuroprotective effects of C-phycocyanin in Parkinson’s disease.

The autophagy-lysosome pathway:a potential target in the chemical and gene therapeutic strategies for Parkinson’s disease

Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.

The pathogenesis of Parkinson’s disease and crosstalk with other diseases

In China,Parkinson’s disease(PD)is the second most prevalent central nervous system(CNS)degenerative illness affecting middle-aged and older persons.Movement disorders including resting tremor,bradykinesia,myotonia,postural instability,and gait instability are the predominant clinical symptoms.The two main types of PD are sporadic and familial,with sporadic PD being the more prevalent of the two.The environment,genetics,mitochondrial dysfunction,oxidative stress,inflammation,protein aggregation and misfolding,loss of trophic factors,cell death,and gut microbiota may all have a role in the etiology of PD.PD is inversely connected with other cancers and positively correlated with COVID-19,diabetes mellitus(DM),melanoma,and ischemic heart disease(IHD)risk.Delaying disease progression,managing motor and non-motor symptoms,and avoiding and controlling dysfunction in the middle and later phases of the disease are the key areas of research and development for its therapy.Presently,the development and progression of PD can be slowed down by using conventional pharmacology,natural items,and innovative technology.This article reviews the pathogenesis of PD,its correlations with other non-genetic diseases,and the research progress of drugs and technologies for alleviating PD.

Developing a Model for Parkinson’s Disease Detection Using Machine Learning Algorithms

Parkinson’s disease(PD)is a chronic neurological condition that progresses over time.People start to have trouble speaking,writing,walking,or performing other basic skills as dopamine-generating neurons in some brain regions are injured or die.The patient’s symptoms become more severe due to the worsening of their signs over time.In this study,we applied state-of-the-art machine learning algorithms to diagnose Parkinson’s disease and identify related risk factors.The research worked on the publicly available dataset on PD,and the dataset consists of a set of significant characteristics of PD.We aim to apply soft computing techniques and provide an effective solution for medical professionals to diagnose PD accurately.This research methodology involves developing a model using a machine learning algorithm.In the model selection,eight different machine learning techniques were adopted:Namely,Random Forest(RF),Decision Tree(DT),Support Vector Machine(SVM),Naïve Bayes(NB),Light Gradient Boosting Machine(LightGBM),K-Nearest Neighbours(KNN),Extreme Gradient Boosting(XGBoost),and Logistic Regression(LR).Subsequently,the concentrated models were validated through 10-fold Cross-Validation and Receiver Operating Characteristic(ROC)—Area Under the Curve(AUC).In addition,GridSearchCV was utilised to measure each algorithm’s best parameter;eventually,the models were trained through the hyperparameter tuning approach.With 98%accuracy,LightGBM had the highest accuracy in this study.RF,KNN,and SVM came in second with 96%accuracy.Furthermore,the performance scores of NB and LR were recorded to be 76%and 83%,respectively.It is to be mentioned that after applying 10-fold cross-validation,the average performance score of LightGBM accounted for 93%.At the same time,the percentage of ROC-AUC appeared at 0.92,which indicates that this LightGBM model reached a satisfactory level.Finally,we extracted meaningful insights and figured out potential gaps on top of PD.By extracting meaningful insights and identifying potential gaps,our study contributes to the significance and impact of PD research.The application of advanced machine learning algorithms holds promise in accurately diagnosing PD and shedding light on crucial aspects of the disease.This research has the potential to enhance the understanding and management of PD,ultimately improving the lives of individuals affected by this condition.

Pathogenic genes associated with Parkinson’s disease:molecular mechanism overview

Parkinson’s disease(PD)is a common neurodegenerative disease in the elderly,accounting for more than 1%of the population aged 65 years.Monogenic inheritance is relatively rare in PD,accounting for approximately 5%to 10%of PD patients,and there is a growing body of evidence suggesting that multiple genetic risk factors play a significant role in the pathogenesis of PD.Several groups have identified and reported a number of genes carrying mutations associated with affected family members.Mutated genes associated with PD are also candidates for idiopathic PD,and these genes may also carry other mutation sites that increase risk.When multiple genetic risk factors are combined,the risk of PD is increased to a greater extent,and to unravel the pathogenic pathways that lead to different forms of PD.This review focuses on the association of PD genes,such as Parkinson Disease 1-24(PARK1-24),glucosylceramidase(GBA),GTP cyclohydrolase 1(GCH1),fibroblast growth factor 20(FGF20),nuclear receptor-related factor 1(NURR1),NUS1 dehydrodolichyl diphosphate synthase subunit(NUS1),diacylglycerol Lipase Beta(DAGLB),transmembrane protein(TMEM),ubiquinol-cytochrome c reductase core protein 1(UQCRC1),glycoprotein non-metastatic melanoma protein B protein(GPNMB),dynactin 1(DCTN1),LDL receptor related protein 10(LRP10),monoamine oxidase(MAO),ataxin 2(ATXN2),microtubule associated protein tau(MAPT),pantothenate kinase 2(PANK2),spastic parapplegia type 11(SPG11),polymer gamma(POLG),TATA-box binding protein associated factor 1(TAF1),dual specificity tyrosine phosphorylation regulated kinase 1A(Dyrk1a),and crystallin alpha A(CRYAA),with the pathogenesis of PD.We introduce what is currently known about the molecular genetics of PD to help explain the molecular mechanisms leading to the neurodegenerative disease.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson’s disease

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

The cGAS-STING-interferon regulatory factor 7 pathway regulates neuroinflammation in Parkinson's disease

Interferon regulatory factor 7 plays a crucial role in the innate immune response.However,whether interferon regulatory factor 7-mediated signaling contributes to Parkinson's disease remains unknown.Here we report that interferon regulatory factor 7 is markedly up-regulated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease and co-localizes with microglial cells.Both the selective cyclic guanosine monophosphate adenosine monophosphate synthase inhibitor RU.521 and the stimulator of interferon genes inhibitor H151 effectively suppressed interferon regulatory factor 7 activation in BV2 microglia exposed to 1-methyl-4-phenylpyridinium and inhibited transformation of mouse BV2 microglia into the neurotoxic M1 phenotype.In addition,si RNA-mediated knockdown of interferon regulatory factor 7 expression in BV2 microglia reduced the expression of inducible nitric oxide synthase,tumor necrosis factorα,CD16,CD32,and CD86 and increased the expression of the anti-inflammatory markers ARG1 and YM1.Taken together,our findings indicate that the cyclic guanosine monophosphate adenosine monophosphate synthase-stimulator of interferon genes-interferon regulatory factor 7 pathway plays a crucial role in the pathogenesis of Parkinson's disease.

Exercise and exerkine upregulation:Brain-derived neurotrophic factor as a potential non-pharmacological therapeutic strategy for Parkinson’s disease

Physical activity and exercise have several beneficial roles in enhancing both physiological and psychological well-being of an individual.In addition to aiding the regulation of aerobic and anaerobic metabolism,exercise can stimulate the synthesis of exerkine hormones in the circulatory system.Among several exerkines that have been investigated for their therapeutic potential,Brain-derived neurotrophic factor(BDNF)is considered the most promising candidate,especially in the management of neurodegenerative diseases.Owing to the ability of physical activity to enhance BDNF synthesis,several experimental studies conducted so far have validated this hypothesis and produced satisfactory results at the pre-clinical level.This review highlights some of the recent animal model studies that have evaluated the efficiency of exercise in enhancing BDNF synthesis and promoting neuroprotective effects.Further,this review focuses on understanding the therapeutic benefits of exercise-induced exerkine synthesis as a non-pharmacological strategy in Parkinson’s disease(PD).Regarding physical activity and exerkine induction,the neuromuscular electrical stimulation(NMES)strategy could be considered as an alternate treatment modality for patients affected with PD.