Etiology Of Parkinson's Disease Research Articles

The proteomics behind clinical and temporal changes in Parkinson's Disease: a literature review

Parkinson's disease (PD) is characterized by the dopaminergic neuron's progressive neurodegeneration, which is chronic and results in movement and behavioral disorders. There are still many gaps in the PD etiology and pathogenesis. Thus, aiming to strengthen the evidence that serves as a tool for diagnostic aid and future treatments, this systematic review aims to relate and analyze studies on the PARK proteomics, that is, the class of expressed park proteins that are associated with pathogenesis, PD clinical changes, and temporal effects. 261 papers were selected for eligibility analysis based on their title and abstract, resulting in 56 papers, with a full reading, included in this study. The observed result leads to the understanding of gene expression for a class of proteins that participate in cellular metabolic pathways associated with the PD etiology. Genetic studies applied to proteomics investigated disease-linked loci of PARK genes and their gene expression to relate the cellular pathways that contribute to PD. It was observed that PARK proteins corroborate the PD pathogenesis, highlighting the hypothesis of change in perception over time. Therefore, exploratory, and systematic studies can guide future investigations and strengthen clinically applied evidence.

Incidence of Parkinson's disease in French women from the E3N cohort study over 27years of follow-up.

Parkinson's disease (PD) is an uncommon disease with a long prodromal period and higher incidence in men than women. Large cohort studies of women with a long follow-up are needed. Within the E3N French cohort study (98,995 women, 40-65years at baseline), we identified 3,584 participants who self-reported PD or used anti-parkinsonian drugs over 27years (1992-2018). We obtained medical records to validate PD diagnosis (definite, probable, possible, no). When medical records were not available, we used a validated algorithm based on drug claims to predict PD status. We retained a PD diagnosis for 1,294 women (medical records, 62%; algorithm, 38%). After exclusion of prevalent/possible cases, cases without age at diagnosis, and women lost to follow-up, our analyses included 98,069 women, of whom 1,200 had incident PD (mean age at diagnosis = 71.8years; incidence rate = 0.494/1,000 person-years). Age-adjusted incidence rates increased over the six first years of follow-up, possibly due to healthy volunteer bias, and remained stable thereafter, similar to incidence rates in women from Western Europe. Forty three percent of PD cases occurred after 20years of follow-up (2012-2018). The cumulative incidence of PD from 50 to 90years was 2.41% (95% confidence interval [CI] = 2.27-2.65). PD incidence was lower in ever than never smokers (hazard ratio = 0.86, 95% CI = 0.76-0.96). In conclusion, we estimated PD incidence rates in French women over a 27-year follow-up, and showed stable incidence between 2002 and 2018. The long follow-up and large sample size make this study a valuable resource to improve our knowledge on PD etiology in women.

Mitochondrial Sirtuins in Parkinson's Disease.

Parkinson's disease (PD), the main risk factor for which is age, is one of the most common neurodegenerative diseases and imposes a substantial burden on affected individuals and the economy. While the aetiology of PD is still largely unclear, substantial evidence indicates that mitochondrial dysfunction, aggregation of α-synuclein (α-syn), oxidative stress, inflammation, and autophagy play major roles in the pathogenesis of PD. Sirtuins are NAD+-dependent protein deacetylases, includeing seven members, i.e., SIRT1-SIRT7. Among these sirtuins, SIRT3, SIRT4 and SIRT5 are located in mitochondria and are called mitochondrial sirtuins. Mitochondrial sirtuins regulate the activity and biological function of mitochondrial proteins through posttranslational modification of substrate proteins. Increasing evidence shows that mitochondrial sirtuins play an important role in degenerative diseases, including PD. Mitochondrial sirtuins exert a beneficial neuroprotective effect in various models of PD. This paper summarizes a large number of studies and discusses the latest research progress on the role of mitochondrial sirtuins in PD, focusing especially on the regulation of the mitochondrial respiratory chain (MRC), oxidative stress, the inflammatory response and autophagy, to provide new insight into the pathogenesis of PD and new targets for the diagnosis and treatment of the disease.

Cytokines, miRNAs, and Antioxidants as Combined Non-invasive Biomarkers for Parkinson's Disease.

Parkinson's disease (PD) is one of the most common long-term degenerative disorders of the CNS that primarily affects the human locomotor system. Owing to the heterogeneity of PD etiology and the lack of appropriate diagnostic tests, blood-based biomarkers became the most promising method for diagnosing PD. Even though various biomarkers for PD have been found, their specificity and sensitivity are not optimum when used alone. Therefore, the aim of this study was directed to evaluate changes in a group of sensitive blood-based biomarkers in the same PD patients compared to healthy individuals. Serum samples were collected from 20 PD patients and 15 age-matched healthy controls. We analyzed serum levels of cytokines (IL10, IL12, and TNF-α), α-synuclein proteins, miRNAs (miR-214, miR-221, and miR-141), and antioxidants (UA, PON1, ARE). Our results showed an increase in sera levels of cytokines in PD patients as well as a positive correlation among them. Also, we found a significant increase in sera levels of α-synuclein protein associated with a decrease in miR-214 which regulates its gene expression. Lastly, we observed a decrease in sera levels of miR-221, miR-141, UA, PON1, and ARE, which have a prominent role against oxidative stress. Because of the many etiologies of PD, a single measure is unlikely to become a useful biomarker. Therefore, to correctly predict disease state and progression, a mix of noninvasive biomarkers is required. Although considerable work has to be done, this study sheds light on the role of certain biomarkers in the diagnosis of PD.

Global Characterization of Peripheral B Cells in Parkinson's Disease by Single-Cell RNA and BCR Sequencing.

Immune system plays important roles in the pathogenesis of Parkinson’s disease (PD). However, the role of B cells in this complex disease are still not fully understood. B cells produce antibodies but can also regulate immune responses. In order to decode the relative contribution of peripheral B cell subtypes to the etiology of PD, we performed single cell RNA and BCR sequencing for 10,466 B cells from 8 PD patients and 6 age-matched healthy controls. We observed significant increased memory B cells and significant decreased naïve B cells in PD patients compared to healthy controls. Notably, we also discovered increased IgG and IgA isotypes and more frequent class switch recombination events in PD patients. Moreover, we identified preferential V and J gene segments of B cell receptors in PD patients as the evidence of convergent selection in PD. Finally, we found a marked clonal expanded memory B cell population in PD patients, up-regulating both MHC II genes (HLA-DRB5, HLA-DQA2 and HLA-DPB1) and transcription factor activator protein 1 (AP-1), suggesting that the antigen presentation capacity of B cells was enhanced and B cells were activated in PD patients. Overall, this study conducted a comprehensive analysis of peripheral B cell characteristics of PD patients, which provided novel insights into the humoral immune response in the pathogenesis of PD.

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis—Parkinson's Disease

Regulatory mechanism of miR-146a on MPTP-induced neuroinflammation in mice with Parkinson's disease


 
 
 
 Purpose: To study the regulatory influence of microRNA-146a (miR-146a) on 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced neuroinflammation in mice with Parkinson's disease (PD).
 Methods: Forty specific pathogen-free (SPF) male C57BL/6 mice were divided into 2 groups: normal control and PD groups. The 2 groups were each divided into 2 subgroups: miR-146a inhibitor and inhibitor control groups. The mRNA and protein expressions of miR-146a, interleukin-1 receptor- associated kinase-1 (IRAK-1) and P65-NF-κB were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblot assay, respectively. Levels of interleukin (IL)-1, IL-6 and TNF-α were assayed by enzyme-linked immunosorbent assay (ELISA).
 Results: The level of expression of miR-146a was significantly and time-dependently increased in PD mice, relative to control (p < 0.05). In PD group, mRNA and protein expressions of IRAK-1 were markedly higher in miR-146a inhibitor group than in inhibitor control (p < 0.05). Protein expression of P65-NF-κB was significantly upregulated in brains of PD mice, relative to normal mice (p < 0.05). Moreover, IL-1, IL-6 and TNF-α levels were significantly higher in brains of PD mice than in control.
 Conclusion: These results show the involvement of miR-146a in the etiology of PD, and that its regulation of neuroinflammation occurs via inhibition of IRAK1 gene expression. This finding may be useful in the development of new anti-PD drugs based on miR-146a.
 
 
 

Emerging Therapeutic Strategies for Parkinson's Disease and Future Prospects: A 2021 Update.

Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.

Analysis of parkin protein using correlation molecular dynamics simulations reveals pathogenic and hyperactive variants

Parkin is an E3 ubiquitin ligase that combines with E2 ligases to shuttle ubiquitin and phosphor-ubiquitin chains onto mitochondrial adapter proteins, which occurs during a process called mitophagy. Mitophagy is critical for normal health of cells when mitochondria malfunction and are sent to lysosomes for recycling via the degradation pathway. However, in Parkinson's disease (PD) patients, there can be individuals with malfunctioning mitochondria that do not have normal mitophagy function, which contributes to their PD etiology.

Targeting α-Synuclein in Parkinson's Disease by Induced Pluripotent Stem Cell Models.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder characterized by motor and non-motor symptoms. To date, no specific treatment to halt disease progression is available, only medication to alleviate symptoms can be prescribed. The main pathological hallmark of PD is the development of neuronal inclusions, positive for α-synuclein (α-syn), which are termed Lewy bodies (LBs) or Lewy neurites. However, the cause of the inclusion formation and the loss of neurons remain largely elusive. Various genetic determinants were reported to be involved in PD etiology, including SNCA, DJ-1, PRKN, PINK1, LRRK2, and GBA. Comprehensive insights into pathophysiology of PD critically depend on appropriate models. However, conventional model organisms fall short to faithfully recapitulate some features of this complex disease and as a matter-of-fact access to physiological tissue is limiting. The development of disease models replicating PD that are close to human physiology and dynamic enough to analyze the underlying molecular mechanisms of disease initiation and progression, as well as the generation of new treatment options, is an important and overdue step. Recently, the establishment of induced pluripotent stem cell (iPSC)-derived neural models, particularly from genetic PD-variants, developed into a promising strategy to investigate the molecular mechanisms regarding formation of inclusions and neurodegeneration. As these iPSC-derived neurons can be generated from accessible biopsied samples of PD patients, they carry pathological alterations and enable the possibility to analyze the differences compared to healthy neurons. This review focuses on iPSC models carrying genetic PD-variants of α-syn that will be especially helpful in elucidating the pathophysiological mechanisms of PD. Furthermore, we discuss how iPSC models can be instrumental in identifying cellular targets, potentially leading to the development of new therapeutic treatments. We will outline the enormous potential, but also discuss the limitations of iPSC-based α-syn models.

Parkinson's Disease in Light of the COVID-19 Pandemic.

In this review we attempt to collate the existing scientific evidence regarding the possible role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the pathophysiology of Parkinson’s disease (PD), as well as to investigate the impact of PD/parkinsonism on the clinical course of the viral infection itself. Since etiology of PD is not completely understood, various studies suggest different potential links between coronavirus disease 2019 (COVID-19) and PD. Suggested connections include, among others, similar prodromal symptoms, renin–angiotensin–aldosterone system involvement, or gut microbiome dysbiosis participation. Despite the initial assumptions that, as a mainly elderly population suffering from rigidity of respiratory muscles, impairment of cough reflex, and dyspnea, PD patients would be more susceptible to viral infection, and would experience a more aggressive course of COVID-19, the published scientific reports contain mutually exclusive data that require further investigation and meta-analysis.

Erinacine A Prevents Lipopolysaccharide-Mediated Glial Cell Activation to Protect Dopaminergic Neurons against Inflammatory Factor-Induced Cell Death In Vitro and In Vivo.

Hericium erinaceus (HE) is a common edible mushroom consumed in several Asian countries and considered to be a medicinal mushroom with neuroprotective effects. Erinacine A (EA) is a bioactive compound in Hericium erinaceus mycelium (HEM) that has been shown to have a neuroprotective effect against neurodegenerative diseases, e.g., Parkinson’s disease (PD). Although the etiology of PD is still unclear, neuroinflammation may play an important role in causing dopaminergic neuron loss, which is a pathological hallmark of PD. However, glial cell activation has a close relationship with neuroinflammation. Thus, this study aimed to investigate the anti-neuroinflammatory and neuroprotective effects of EA on lipopolysaccharide (LPS)-induced glial cell activation and neural damage in vitro and in vivo. For the in vitro experiments, glial cells, BV-2 microglial cells and CTX TNA2 astrocytes were pretreated with EA and then stimulated with LPS and/or IFN-γ. The expression of proinflammatory factors in the cells and culture medium was analyzed. In addition, differentiated neuro-2a (N2a) cells were pretreated with EA or HEM and then stimulated with LPS-treated BV-2 conditioned medium (CM). The cell viability and the amount of tyrosine hydroxylase (TH) and mitogen-activated protein kinases (MAPKs) were analyzed. In vivo, rats were given EA or HEM by oral gavage prior to injection of LPS into the substantia nigra (SN). Motor coordination of the rats and the expression of proinflammatory mediators in the midbrain were analyzed. EA pretreatment prevented LPS-induced iNOS expression and NO production in BV-2 cells and TNF-α expression in CTX TNA2 cells. In addition, both EA and HEM pretreatment significantly increased cell viability and TH expression and suppressed the phosphorylation of JNK and NF- κB in differentiated N2a cells treated with CM. In vivo, both EA and HEM significantly improved motor dysfunction in the rotarod test and the amphetamine-induced rotation test and reduced the expression of TNF-α, IL-1β and iNOS in the midbrain of rats intranigrally injected with LPS. The results demonstrate that EA ameliorates LPS-induced neuroinflammation and has neuroprotective properties.

Challenges in Clinico-Genetic Correlations in Parkinson’s disease (PD). The Role of Copy Number Variants (CNV)

Parkinson’s disease (PD) represents the second most common neurodegenerative disease and remains incurable. Mutations in multiple genes have been linked to monogenic PD (gPD); these monogenic forms, however, represent a small number of cases while in most instances PD appears as idiopathic (iPD). These findings raise the question of whether genetic and idiopathic parkinsonisms constitute the same disease. Nevertheless, monogenic-PD phenotypes and iPD both fulfill MDS criteria for PD, and show evidence of alpha-synuclein aggregates in both conditions. Distinct genetic loci in rare Mendelian forms have been identified as causal mutations, others as possible disease-causing genes, and genome-wide association studies have reported several risk loci, many of them located in the genes associated with the dominant mutations. Not only single-nucleotide polymorphisms (SNPs), but other kinds of DNA molecular defects as well have been spotted as significant disease-causing mutations, including large chromosomal structural rearrangements and copy number variations (CNVs). As their size varies, and detection methodologies have different sensitivity and resolution, CNVs pose a special challenge in genetic studies, and there currently is a debate on the pathogenetic or susceptibility impact of specific CNVs on PD. In this review, through multiple instances of experimental evidence, we analyze the impact on histopathology of the different mutational mechanisms involved in the genesis and etiology of PD. We believe that increasing our knowledge about the changes and implications at tissue level produced by each of those mechanisms will allow to develop much more suitable and personalized potential therapeutic strategies, biomarker identification, as well as disease modeling, agreeing with the precision medicine concept.

Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.

Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson’s disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat “resistant” to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.

Parkinson's Disease and the Metal-Microbiome-Gut-Brain Axis: A Systems Toxicology Approach.

Parkinson’s Disease (PD) is a neurodegenerative disease, leading to motor and non-motor complications. Autonomic alterations, including gastrointestinal symptoms, precede motor defects and act as early warning signs. Chronic exposure to dietary, environmental heavy metals impacts the gastrointestinal system and host-associated microbiome, eventually affecting the central nervous system. The correlation between dysbiosis and PD suggests a functional and bidirectional communication between the gut and the brain. The bioaccumulation of metals promotes stress mechanisms by increasing reactive oxygen species, likely altering the bidirectional gut–brain link. To better understand the differing molecular mechanisms underlying PD, integrative modeling approaches are necessary to connect multifactorial perturbations in this heterogeneous disorder. By exploring the effects of gut microbiota modulation on dietary heavy metal exposure in relation to PD onset, the modification of the host-associated microbiome to mitigate neurological stress may be a future treatment option against neurodegeneration through bioremediation. The progressive movement towards a systems toxicology framework for precision medicine can uncover molecular mechanisms underlying PD onset such as metal regulation and microbial community interactions by developing predictive models to better understand PD etiology to identify options for novel treatments and beyond. Several methodologies recently addressed the complexity of this interaction from different perspectives; however, to date, a comprehensive review of these approaches is still lacking. Therefore, our main aim through this manuscript is to fill this gap in the scientific literature by reviewing recently published papers to address the surrounding questions regarding the underlying molecular mechanisms between metals, microbiota, and the gut–brain-axis, as well as the regulation of this system to prevent neurodegeneration.

Quantifying Levels of Dopaminergic Neuron Morphological Alteration and Degeneration in Caenorhabditis elegans.

Dopamine neuron loss is involved in the pathology of Parkinson's Disease (PD), a highly prevalent neurodegenerative disorder affecting over 10 million people worldwide. Since many details about PD etiology remain unknown, studies investigating genetic and environmental contributors to PD are needed to discover methods of prevention, management, and treatment. Proper characterization of dopaminergic neuronal loss may be relevant not only to PD research, but to other increasingly prevalent neurodegenerative disorders. There are established genetic and chemical models of dopaminergic neurodegeneration in the Caenorhabditis elegans model system, with easy visualization of neurobiology supported by the nematodes' transparency and invariant neuronal architecture. In particular, hermaphroditic C. elegans' dopaminergic neuron morphological changes can be visualized using strains with fluorescent reporters driven by cell-specific promotors such as the dat-1 dopamine transporter gene, which is expressed exclusively in their eight dopaminergic neurons. With the capabilities of this model system and the appropriate technology, many laboratories have studied dopaminergic neurodegeneration. However, there is little consistency in the way the data is analyzed and much of the present literature uses binary scoring analyses that capture the presence of degeneration but not the full details of the progression of neuron loss. Here, we introduce a universal scoring system to assess morphological changes and degeneration in C. elegans' cephalic neuron dendrites. This seven-point scale allows for analysis across a full range of dendrite morphology, ranging from healthy neurons to complete dendrite loss, and considering morphological details including kinks, branching, blebs, and breaks. With this scoring system, researchers can quantify subtle age-related changes as well as more dramatic chemical-induced changes. Finally, we provide a practice set of images with commentary that can be used to train, calibrate, and assess the scoring consistency of researchers new to this method. This should improve within- and between- laboratory consistency, increasing rigor and reproducibility.

Quantifying Levels of Dopaminergic Neuron Morphological Alteration and Degeneration in <em>Caenorhabditis elegans</em>

Dopamine neuron loss is involved in the pathology of Parkinson's Disease (PD), a highly prevalent neurodegenerative disorder affecting over 10 million people worldwide. Since many details about PD etiology remain unknown, studies investigating genetic and environmental contributors to PD are needed to discover methods of prevention, management, and treatment. Proper characterization of dopaminergic neuronal loss may be relevant not only to PD research, but to other increasingly prevalent neurodegenerative disorders. There are established genetic and chemical models of dopaminergic neurodegeneration in the Caenorhabditis elegans model system, with easy visualization of neurobiology supported by the nematodes' transparency and invariant neuronal architecture. In particular, hermaphroditic C. elegans' dopaminergic neuron morphological changes can be visualized using strains with fluorescent reporters driven by cell-specific promotors such as the dat-1 dopamine transporter gene, which is expressed exclusively in their eight dopaminergic neurons. With the capabilities of this model system and the appropriate technology, many laboratories have studied dopaminergic neurodegeneration. However, there is little consistency in the way the data is analyzed and much of the present literature uses binary scoring analyses that capture the presence of degeneration but not the full details of the progression of neuron loss. Here, we introduce a universal scoring system to assess morphological changes and degeneration in C. elegans' cephalic neuron dendrites. This seven-point scale allows for analysis across a full range of dendrite morphology, ranging from healthy neurons to complete dendrite loss, and considering morphological details including kinks, branching, blebs, and breaks. With this scoring system, researchers can quantify subtle age-related changes as well as more dramatic chemical-induced changes. Finally, we provide a practice set of images with commentary that can be used to train, calibrate, and assess the scoring consistency of researchers new to this method. This should improve within- and between- laboratory consistency, increasing rigor and reproducibility.

Elucidating the Neuroprotective Role of PPARs in Parkinson's Disease: A Neoteric and Prospective Target.

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.

Combining Automated Organoid Workflows with Artificial Intelligence-Based Analyses: Opportunities to Build a New Generation of Interdisciplinary High-Throughput Screens for Parkinson's Disease and Beyond.

Parkinson's disease (PD) is the second most common neurodegenerative disease and primarily characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. Despite decades of research and the development of various disease model systems, there is no curative treatment. This could be due to current model systems, including cell culture and animal models, not adequately recapitulating human PD etiology. More complex human disease models, including human midbrain organoids, are maturing technologies that increasingly enable the strategic incorporation of the missing components needed to model PD in vitro. The resulting organoid-based biological complexity provides new opportunities and challenges in data analysis of rich multimodal data sets. Emerging artificial intelligence (AI) capabilities can take advantage of large, broad data sets and even correlate results across disciplines. Current organoid technologies no longer lack the prerequisites for large-scale high-throughput screening (HTS) and can generate complex yet reproducible data suitable for AI-based data mining. We have recently developed a fully scalable and HTS-compatible workflow for the generation, maintenance, and analysis of three-dimensional (3D) microtissues mimicking key characteristics of the human midbrain (called "automated midbrain organoids," AMOs). AMOs build a reproducible, scalable foundation for creating next-generation 3D models of human neural disease that can fuel mechanism-agnostic phenotypic drug discovery in human in vitro PD models and beyond. Here, we explore the opportunities and challenges resulting from the convergence of organoid HTS and AI-driven data analytics and outline potential future avenues toward the discovery of novel mechanisms and drugs in PD research. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A systematic review of molecular approaches that link mitochondrial dysfunction and neuroinflammation in Parkinson's disease.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that affects 1% of the population worldwide. Etiology of PD is likely to be multi-factorial such as protein misfolding, mitochondrial dysfunction, oxidative stress, and neuroinflammation that contributes to the pathology of Parkinson's disease (PD), numerous studies have shown that mitochondrial dysfunction may play a key role in the dopaminergic neuronal loss. In multiple ways, the two most important are the activation of neuroinflammation and mitochondrial dysfunction, while mitochondrial dysfunction could cause neuroinflammation and vice versa. Thus, the mitochondrial proteins are the highly promising target for the development of PD. However, the limited amount of dopaminergic neurons prevented the detailed investigation of Parkinson's disease with regard to mitochondrial dysfunction. Both genetic and environmental factors are also associated with mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provide direct evidence linking mitochondrial dysfunction to PD. A decrease of mitochondrial complex I activity is observed in PD brain and in neurotoxin- or genetic factor-inducedin vitroandin vivomodels. Moreover, PINK1, Parkin, DJ-1 and LRRK2 mitochondrial PD gene products have important roles in mitophagy, a cellular process that clear damaged mitochondria.This review paper would discuss the evidence for the mitochondrial dysfunction and neuroinflammation in PD.