Treatment Of Parkinson's Disease Research Articles

Efficacy and safety of acupuncture therapy for Parkinson’s disease with neuropsychiatric symptoms: protocol for a systematic review and meta-analysis

IntroductionNeuropsychiatric symptoms (NPS) are common non-motor symptoms among patients with Parkinson’s disease (PD) and significantly impact their overall quality of life detrimentally. Several studies have reported the clinical effect of...

Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and in-silico study.

Parkinson's disease (PD) stands as a challenging neurodegenerative condition characterized by the emergence of Lewy Bodies (LBs), intracellular inclusions within dopaminergic neurons. These LBs harbor various proteins, prominently including α-Synuclein (Syn) aggregates, implicated in disease pathology. A promising avenue in PD treatment involves targeting Syn aggregation. Recent findings from our research have shown that 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) possess the ability to impede the formation of Syn fibrils by disrupting the aggregation process. Notably, these compounds primarily engage in noncovalent interactions with the protein, leading to the formation of off-pathway oligomers that deter fibril growth. Through proteolysis studies and mass spectrometry (MS) analysis, we have identified potential covalent modifications of Syn in the presence of DOPAC, although the exact site remains elusive. Employing molecular dynamics simulations, we delved into how DOPAC-induced covalent alterations might affect the mechanism of Syn aggregation. Our findings indicate that the addition of a covalent adduct on certain residues enhances fibril flexibility without compromising its secondary structure stability. Furthermore, in the monomeric state, the modified residue fosters novel bonding interactions, thereby influencing long-range interactions between the N- and C-termini of the protein.

From lab bench to hope: a review of gene therapies in clinical trials for Parkinson's disease and challenges.

Parkinson's disease (PD) is a chronic neurological disorder that is identified by a characteristic combination of symptoms such as bradykinesia, resting tremor, rigidity, and postural instability. It is the second most common neurodegenerative disease after Alzheimer's disease and is characterized by the progressive loss of dopamine-producing neurons in the brain. Currently, available treatments for PD are symptomatic and do not prevent the disease pathology. There is growing interest in developing disease-modifying therapy that can reduce disease progression and improve patients' quality of life. One of the promising therapeutic approaches under evaluation is gene therapy utilizing a viral vector, adeno-associated virus (AAV), to deliver transgene of interest into the central nervous system (CNS). Preclinical studies in small animals and nonhuman primates model of PD have shown promising results utilizing the gene therapy that express glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), aromatic L-amino acid decarboxylase (AADC), and glutamic acid decarboxylase (GAD). This study provides a comprehensive review of the current state of the above-mentioned gene therapies in various phases of clinical trials for PD treatment. We have highlighted the rationale for the gene-therapy approach and the findings from the preclinical and nonhuman primates studies, evaluating the therapeutic effect, dose safety, and tolerability. The challenges associated with gene therapy for heterogeneous neurodegenerative diseases, such as PD, have also been described. In conclusion, the review identifies the ongoing promising gene therapy approaches in clinical trials and provides hope for patients with PD.

Lixisenatide in early parkinson's disease: efficacy, safety, and future directions: a correspondence.

Parkinson's disease (PD) presents as a complex neurodegenerative disorder characterized by motor and non-motor symptoms, resulting from dopaminergic neuron degeneration. Current treatment strategies primarily aim to alleviate symptoms through pharmacotherapy and supportive therapies. However, emerging research explores novel therapeutic avenues, including the repurposing of drugs like lixisenatide, a GLP-1 receptor agonist initially developed for type 2 diabetes. This correspondence summarizes a phase 2 clinical trial investigating lixisenatide's efficacy in early PD, demonstrating a potential for mitigating motor disability progression. Findings reveal a marginal improvement or stabilization in motor function among lixisenatide-treated individuals compared to placebo, emphasizing its therapeutic promise. Nonetheless, the emergence of gastrointestinal adverse events underscores the need for careful monitoring and management. Further extensive trials are warranted to delineate lixisenatide's efficacy and safety profile, fostering collaborative efforts towards precision treatments in PD.

Orexin B protects dopaminergic neurons from 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity associated with reduced extracellular signal-regulated kinase phosphorylation.

The loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a major pathological hallmark of Parkinson's disease (PD). Orexin B (OXB) has been reported to promote the growth of DA neurons. However, the roles of OXB in the degeneration of DA neurons still remained not fully clear. An in vivo PD model was constructed by administrating 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Pole test was performed to investigate the motor function of mice and the number of DA neurons was detected by immunofluorescence (IF). A PD cell model was established by treating SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP+). OXB was added to the culture medium 2h after MPP + treatment. Microscopic analysis was carried out to investigate the function of OXB in the cell model of PD 24h after MPP + challenge. RNA-Seq analysis of the PD cell model was performed to explore the possible mechanisms. Western blot was used to detect the phosphorylation levels of extracellular signal-regulated kinase (ERK). OXB significantly decreased the DA neurons death caused by MPTP, alleviated MPP+-induced neurotoxicity in SH-SY5Y cells, and robustly enhanced the weight and motor ability of PD mice. Besides, RNA-Seq analysis demonstrated that the mitogen-activated protein kinase (MAPK) pathway was involved in the pathology of PD. Furthermore, MPP + led to increased levels of phosphorylation of ERK (p-ERK), OXB treatment significantly decreased the levels of p-ERK in MPP+-treated SH-SY5Y cells. This study demonstrated that OXB exerts a neuroprotective role associated with reduced ERK phosphorylation in the PD model. This suggests that OXB may have therapeutic potential for treatment of PD.

Levodopa infusion therapies for Parkinson disease.

to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site. Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.

CAP2 contributes to Parkinson’s disease diagnosed by neutrophil extracellular trap-related immune activity

IntroductionNeutrophil extracellular traps (NETs) constitute a crucial element of the immune system, and dysfunction in immune responses is implicated in the susceptibility and progression of Parkinson's disease (PD). Nevertheless, the mechanism connecting PD and NETs remains unclear. This study aims to uncover potential NETs-related immune biomarkers and elucidate their role in PD pathogenesis.MethodsThrough differential gene analysis of PD and NETs in GSE7621 datasets, we identified two PD subtypes and explored potential biological pathways. Subsequently, using ClusterWGCNA, we pinpointed pertinent genes and developed clinical diagnostic models. We then optimized the chosen model and evaluated its association with immune infiltration. Validation was conducted using the GSE20163 dataset. Screening the single-cell dataset GSE132758 revealed cell populations associated with the identified gene. ResultsOur findings identified XGB as the optimal diagnostic model, with CAP2 identified as a pivotal gene. The risk model effectively predicted overall diagnosis rates, demonstrating a robust correlation between infiltrating immune cells and genes related to the XGB model. DiscussionIn conclusions, we identified PD subtypes and diagnostic genes associated with NETs, highlighting CAP2 as a pivotal gene. These findings have significant implications for understanding potential molecular mechanisms and treatments for PD.

A Plant Model of α-Synucleinopathy: Expression of α-Synuclein A53T Variant in Hairy Root Cultures Leads to Proteostatic Stress and Dysregulation of Iron Metabolism

Synucleinopathies, typified by Parkinson’s disease (PD), entail the accumulation of α-synuclein (αSyn) aggregates in nerve cells. Various αSyn mutants, including the αSyn A53T variant linked to early-onset PD, increase the propensity for αSyn aggregate formation. In addition to disrupting protein homeostasis and inducing proteostatic stress, the aggregation of αSyn in PD is associated with an imbalance in iron metabolism, which increases the generation of reactive oxygen species and causes oxidative stress. This study explored the impact of αSyn A53T expression in transgenic hairy roots of four medicinal plants (Lobelia cardinalis, Artemisia annua, Salvia miltiorrhiza, and Polygonum multiflorum). In all tested plants, αSyn A53T expression triggered proteotoxic stress and perturbed iron homeostasis, mirroring the molecular profile observed in human and animal nerve cells. In addition to the common eukaryotic defense mechanisms against proteostatic and oxidative stresses, a plant stress response generally includes the biosynthesis of a diverse set of protective secondary metabolites. Therefore, the hairy root cultures expressing αSyn A53T offer a platform for identifying secondary metabolites that can ameliorate the effects of αSyn, thereby aiding in the development of possible PD treatments and/or treatments of synucleinopathies.

Immunophenotyping Tracks Motor Progression in Parkinson's Disease Associated with a TH Mutation.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with genetic factors accounting for about 15% of cases. There is a significant challenge in tracking disease progression and treatment response, crucial for developing new therapies. Traditional methods like imaging, clinical monitoring, and biomarker analysis have not conclusively tracked disease progression or treatment response in PD. Our previous research indicated that PD patients with increased dopamine transporter (DAT) and tyrosine hydroxylase (TH) in peripheral blood mononuclear cells (PBMCs) might show disease progression and respond to levodopa treatment. This study evaluates whether DAT- and TH-expressing PBMCs can monitor motor progression in a PD patient with a heterozygous TH mutation. We conducted a longitudinal follow-up of a 46-year-old female PD patient with a TH mutation, assessing her clinical features over 18 months through DaT scans and PBMC immunophenotyping. This was compared with idiopathic PD patients (130 subjects) and healthy controls (80 age/sex-matched individuals). We found an increase in DAT+ immune cells concurrent with worsening motor scores (UPDRS-III). Following levodopa therapy, unlike idiopathic PD patients, TH+ immune cell levels in this patient remained high even as her motor scores improved. Longitudinal immunophenotyping in this PD patient suggests DAT+ and TH+ PBMCs as potential biomarkers for tracking PD progression and treatment efficacy, supporting further exploration of this approach in PD research.

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Staged bilateral FUS-STN. Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

Trait Impulsivity as a Feature of Parkinson's Disease Treatment and Progression.

Heightened trait impulsivity in both subclinical and pathological senses is becoming increasingly recognised in Parkinson's disease (PD). Impulsive behaviours and impulse control disorders (ICDs) are a consequence of perturbation to the rewards pathway leading individuals to conduct activities in a repetitive, excessive, and maladaptive fashion. Commonly linked to PD, heightened trait impulsivity has been found to primarily manifest in the forms of hypersexuality, pathological gambling, compulsive shopping, and binge eating, all of which may significantly impact social and financial standing. Subsequent burden to quality of life for both individuals with PD and caregivers are common. Although risk factors and indicators for ICDs in PD are currently lacking, it is recognised that the condition is often precipitated by dopamine replacement therapies, primarily dopamine agonist administration. While this nonmotor symptom is being increasingly diagnosed in PD populations, it remains relatively elusive in comparison to its motor counterparts. Through discussion of impulsivity characteristics, neuroanatomy, and neurochemistry, in addition to reviewing existing research on the potential contributing factors to impulsivity in PD, this review highlights impulsivity as a significant and detrimental PD symptom. Thus, emphasising the imperative need to establish efficacious diagnostic tools and treatments.

Chamuangone-enriched rice bran oil ameliorates neurodegeneration in haloperidol-induced Parkinsonian rat model via modulation of neuro-inflammatory mediators and suppression of oxidative stress markers

A natural bioactive compound chamuangone extracted from Thai salad Garcinia cowa leaves exhibited robust medicinal properties, targeting central oxidative stress pathways, and having neuroprotective potential. Chamuangone-enriched rice bran oil (CERBO), with 1.97 mg/mL chamuangone, was obtained through green extraction. The study was designed to evaluate the anti-Parkinson’s activity of CERBO in the haloperidol-induced Parkinsonian rat model. Animals were categorized into six groups as control, disease control and treatment groups. Parkinson’s disease (PD)-like symptoms were induced by administration of haloperidol 1 mg/kg, intraperitoneally; CERBO treatment groups received 2.5, 5, and 7.5 mg/kg orally before the administration of haloperidol for 21 days. Neurobehavioral, biochemical, neurochemical, and histopathological studies along with gene expression analysis were performed at the completion of the study. CERBO markedly recover the motor and non-motor PD-like symptoms in treatment groups dose-dependently. The levels of antioxidant enzymes, such as catalase, superoxide dismutase, reduced glutathione, and glutathione peroxidase, increased, while malondialdehyde levels decreased dose-dependently in CERBO-treated groups. CERBO dose-dependent elevations were observed in neurotransmitters (dopamine, serotonin, and noradrenaline). PD-associated specific biomarker (α-synuclein) decreased dose-dependently with downregulation in messenger RNA expression of neuro-inflammatory mediators (interleukin α, interleukin 1β, and tumor necrosis factor-α). Histopathological studies revealed recovery in neuronal loss, formation of Lewy’s bodies, and neurofibrillary tangles in the treatment groups. It was concluded from the data that CERBO possessed good anti-Parkinson’s activity and could be a novel, safe, and effective remedy for the treatment of PD.

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson’s disease

BackgroundIntranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson’s disease (PD). We investigated the safety and tolerability of this treatment...

Black Phosphorus Nanosheets Protect Neurons by Degrading Aggregative α-syn and Clearing ROS in Parkinson's Disease.

Although evidence indicates that the abnormal accumulation of α-synuclein (α-syn) in dopamine neurons of the substantia nigra is the main pathological feature of Parkinson's disease (PD), no compounds that have both α-syn antiaggregation and α-syn degradation functions have been successful in treating the disease in the clinic. Here, it is shown that black phosphorus nanosheets (BPNSs) interact directly with α-syn fibrils to trigger their disaggregation for PD treatment. Moreover, BPNSs have a specific affinity for α-syn through van der Waals forces. And BPNSs are found to activate autophagy to maintain α-syn homeostasis, improve mitochondrial dysfunction, reduce reactive oxygen species levels, and rescue neuronal death and synaptic loss in PC12 cells. It is also observed that BPNSs penetrate the blood-brain barrier and protect against dopamine neuron loss, alleviating behavioral disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model and hA53T α-syn transgenic mice. Together, the study reveals that BPNSs have the potential as a novel integrated nanomedicine for clinical diagnosis and treatment of neurological diseases.

Exploring cognitive reserve’s influence: unveiling the dynamics of digital telerehabilitation in Parkinson’s Disease Resilience

Telerehabilitation is emerging as a promising digital method for delivering rehabilitation to Parkinson’s Disease (PD) patients, especially in the early stages to promote brain resilience. This study explores how cognitive reserve (CR), the brain’s ability to withstand aging and disease, impacts the effectiveness of telerehabilitation. It specifically examines the influence of lifelong cognitive activities on the relationship between neural reserve and improved functional abilities following rehabilitation. In the study, 42 PD patients underwent a 4-month neuromotor telerehabilitation program. CR proxies were assessed using the Cognitive Reserve Index questionnaire (CRIq), brain changes via 3T-MRI, and functional response through changes in the 6-Minute Walk Distance (6MWD). Participants were divided into responders (n = 23) and non-responders (n = 19) based on their 6MWD improvement. A multiple regression model was run to test significant predictors of 6MWD after treatment in each group. The results revealed a significant correlation between 6MWD and CRIq scores, but only among responders. Notably, the CRIq Leisure-Time sub-index, along with baseline 6MWD, were predictors of post-treatment 6MWD. These findings highlight CR’s role in enhancing the benefits of telerehabilitation on PD patients’ neuromotor functions. Clinically, these results suggest that neurologists and clinicians should consider patients’ lifestyles and cognitive engagement as important factors in predicting and enhancing the outcomes of telerehabilitation. The study underscores the potential of CR as both a predictor and booster of telerehabilitation’s effects, advocating for a personalized approach to PD treatment that takes into account individual CR levels.

Intranasal Administration of Umbilical Cord Mesenchymal Stem Cell Exosomes Alleviates Parkinson's Disease

Parkinson's disease (PD) is a common and complex neurodegenerative disease. This disease is typically characterized by the formation of Lewy bodies in multiple brain regions and dopaminergic neuronal loss in the substantia nigra pars compacta, resulting in non-motor symptoms (e.g., olfactory deficits) and motor dysfunction in the late stages. There is yet no effective cure for Parkinson’s disease. Considering the neuroprotective effects of exosomes, we investigated whether intranasal administration of umbilical cord mesenchymal stem cell exosomes could improve behavioral functions in PD mice. First, exosomes were endocytosed by the cells in vitro and in vivo, indicating that exosomes can cross the blood–brain barrier. Second, we found that both motor and non-motor functions of the PD models were effectively improved during intranasal exosomes treatment. Finally, the activity of olfactory bulb neurons was improved and the loss of dopaminergic neurons in the substantia nigra pars compacta was reversed. Moreover, exosomes attenuated microglia and astrocyte activation, leading to a low level of inflammation in the brain. In conclusion, our study provided a new reference for the clinical application of exosomes in the treatment of PD.

The TLR4/NF-κB/NLRP3 and Nrf2/HO-1 pathways mediate the neuroprotective effects of alkaloids extracted from Uncaria rhynchophylla in Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder with limited therapeutic options available. Neuroinflammation plays an important role in the occurrence and development of PD. Alkaloids extracted from Uncaria rhynchophylla (URA), have emerged as a potential neuroprotective agent because of its anti-inflammatory and anti-oxidant properties. Nevertheless, the underlying mechanism by which URA exerts neuroprotective effects in PD remains obscure. The main aim of this study was to investigate the neuroprotective effects and underlying mechanism of URA in the treatment of PD through in vivo and in vitro models, focusing on the neuroinflammation and oxidative stress pathways. The protective effects of URA against PD were evaluated by neurobehavioral tests, immunohistochemistry, serum biochemical assays, and real-time quantitative polymerase chain reaction in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. The role of the TLR4/NF-κB/NLRP3 pathway and the Nrf2/HO-1 pathway in URA-mediated effects was examined in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a microglia-neuron coculture system. URA significantly alleviated motor deficits and dopaminergic neurotoxicity, and reversed the abnormal secretion of inflammatory and oxidative stress factors in the serum of MPTP-induced mice. URA suppressed the gene expression of Toll-like receptor 4 (TLR4), NOD-like receptor protein 3, and cyclooxygenase 2 (COX2) in the striatum of PD mice. Further studies indicated that URA inhibited activation of the TLR4/NF-κB/NLRP3 pathway and enhanced activation of the Nrf2/HO-1 pathway, reduced reactive oxygen species (ROS) production, and reversed the secretion of inflammatory mediators in LPS-stimulated BV-2 microglial cells, thereby alleviating neuroinflammatory damage to SH-SY5Y neuronal cells. URA exerted neuroprotective effects against PD mainly by the inhibition of the TLR4/NF-κB/NLRP3 pathway and activation of the Nrf2/HO-1 antioxidant pathway, highlighting URA as a promising candidate for PD treatment.

Cognitive compromise in a cohort of patients from Colombia with DBS for Parkinson's disease treatment

Cognitive compromise in a cohort of patients from Colombia with DBS for Parkinson's disease treatment

Unraveling the characteristics of Parkinson's Disease through neuroimaging: Insights and future directions

Parkinson's disease (PD) is a neurodegenerative disease with a high degree of patient heterogeneity, and as of 2016 there are approximately 6.1 million PD patients worldwide. PD has a high proportion of patients with intermediate to advanced disease and a high rate of disability, and clinical diagnosis and treatment are difficult due to the lack of neuromarkers to identify disease states and the inability to quantify the effects of treatment in PD. In recent years, many researchers have explored specific changes in brain activity in PD based on electrophysiological and neuroimaging data. Electroencephalography, with its high temporal resolution and rich frequency domain information, and functional magnetic resonance imaging, with its high spatial resolution, have become the main tools to characterize the state of brain activity in PD in recent years. This paper analyses some of the available data on the characteristics of PD through two neuroimaging techniques commonly used in the disease. It concludes with the prospect of being able to establish uniform criteria for determining PD.

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

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