Misfolding Of Alpha-synuclein Research Articles

Alpha-synuclein misfolding as fluid biomarker for Parkinson’s disease measured with the iRS platform

Misfolding and aggregation of alpha-synuclein (αSyn) play a key role in the pathophysiology of Parkinson’s disease (PD). Despite considerable advances in diagnostics, an early and differential diagnosis of PD still represents a major challenge. We innovated the immuno-infrared sensor (iRS) platform for measuring αSyn misfolding. We analyzed cerebrospinal fluid (CSF) from two cohorts comprising PD cases, atypical Parkinsonian disorders, and disease controls. We obtained an AUC of 0.90 (n = 134, 95% CI 0.85–0.96) for separating PD/MSA from controls by determination of the αSyn misfolding by iRS. Using two thresholds divided individuals as unaffected/affected by misfolding with an intermediate area in between. Comparing the affected/unaffected cases, controls versus PD/MSA cases were classified with 97% sensitivity and 92% specificity. The spectral data revealed misfolding from an α-helical/random-coil αSyn in controls to β-sheet enriched αSyn in PD and MSA cases. Moreover, a first subgroup analysis implied the potential for patient stratification in clinically overlapping cases. The iRS, directly measuring all αSyn conformers, is complementary to the αSyn seed-amplification assays (SAAs), which however only amplify seeding competent conformers.

Effects of herbaceous bioflavonoid herbacetin on oxidative stress, and alpha-synuclein regulation, programmed cell death in a Parkinson illness

Background Herbacetin, a flavonoid present in many types of herbs, which include linaceae, ephedraceae, and crassulaceae, exhibits a range of medicinal properties. 1-methyl-4-phenylpyridinium (MPP+) is one of the neurotoxins used in cell-based Parkinson’s disease (PI) models. Whereas the precise chemical mechanism of iron association with free radical cell damage and apoptosis is yet unknown, intracellular irons are a key factor for MPP+-derived apoptosis. Methods We examine whether the antiapoptotic properties of flaxseed bioflavonoid herbacetin (HB) are associated with the stimulation of the intrinsic caspase-dependent pathway and exposing of MPP+ caused neuronal death in the human dopaminergic neuroblastoma cells. Four groups were created out of the cells. Groups I, II, III, and IV are the control, HB+MPP+, MPP+, and HB, respectively. Following a 24-hour incubation period, the cells were subjected to several parameters. Results We discovered in neuroblastoma cells that HB dramatically reduced the cell death induced by MPP+. Additionally, HB significantly reduced the formation of ROS and counteracted the reduction in MMP resulting from MPP+ treatment. HB reduces the stimulation of the intrinsic caspase-dependent apoptotic mechanism and suppresses the MPP+-mediated apoptotic signalling pathway. Furthermore, HB predicted a better binding interaction with alpha-synuclein and drastically decreased alpha-synuclein expression and accumulation in neuroblastoma cells. Conclusion Consequently, our findings imply that HB shields neurons by reducing oxidative stress, alpha-synuclein misfolding in neuroblastoma, and apoptosis prompts the death of neuroblastoma cells.

Molecular mechanisms and biomarkers in neurodegenerative disorders: a comprehensive review.

Neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD), are significant global health challenges, owing to their profound impact on cognitive, motor, and behavioral functions. The etiology and progression of these disorders are influenced by a complex interplay of environmental factors and genetic predispositions with specific genetic markers, such as mutations in the APOE and HTT genes, which play pivotal roles. Current therapeutic interventions predominantly focus on symptom management; however, emerging strategies, including gene therapies, anti-amyloid agents, and neuroprotective approaches, are designed to directly target the underlying disease mechanisms. Advances in biomarker discovery and imaging methodologies have emerged as essential tools for early diagnosis and monitoring of therapeutic efficacy in these disorders. In the context of AD, cerebrospinal fluid (CSF) amyloid-beta (Aβ) and tau levels, along with positron emission tomography (PET) imaging, are well-established biomarkers. Similarly, CSF alpha-synuclein and dopamine transporter (DAT) imaging have been employed as diagnostic tools for PD. Moreover, emerging biomarkers, such as blood-based tau and the Aβ42/40 ratio for AD, as well as the neurofilament light chain (NfL) for ALS and PD, hold promise for enhancing early diagnostic accuracy and facilitating the longitudinal assessment of disease progression. This study comprehensively examined the molecular mechanisms underlying these neurodegenerative disorders, focusing on amyloid-beta plaque deposition and tau protein aggregation in AD, alpha-synuclein misfolding in PD, and aberrant protein aggregation in ALS and HD, thereby contributing to a deeper understanding of the pathophysiological basis of these disorders.

Immune landscape of the enteric nervous system differentiates Parkinson's disease patients from controls: The PADUA-CESNE cohort

Immune landscape of the enteric nervous system differentiates Parkinson's disease patients from controls: The PADUA-CESNE cohort

Unravelling the role of nutraceutical supplements in treatment of Parkinson’s Disease

Parkinson’s Disease (PD) causes motor dysfunction that usually begins in the elderly population. The prevalence rate of PD is increasing significantly. Currently available therapies are able to manage the disease, however, they have certain side effects associated with long term usage. Hence, there is a dire need to bring therapies that can offer good treatment to PD with less side effects. Recent research has revealed that food supplements which are specifically rich in antioxidants and vitamins have shown better efficacy against PD with a better safety profile. Hence, the present study focuses on the role of nutraceuticals in treatment of PD. Nutritional supplements targeting PD pathology were explored between 2016 and 2022 through Scopus, google scholar and PubMed. The review deciphered the neuroprotective benefits of vitamins, minerals, natural compounds, and phytochemicals that might procrastinate or help in the prevention of PD’s progression by targeting some of the major pathological mechanisms such as oxidative stress, neuroinflammation, misfolding of alpha-synuclein, and mitochondrial dysfunction. Various studies indicating the potential of nutraceutical supplements are discussed in detail.

In vivo effects of the alpha-synuclein misfolding inhibitor minzasolmin supports clinical development in Parkinson’s disease

Direct targeting of alpha-synuclein (ASYN) has emerged as a disease-modifying strategy for Parkinson’s disease and other synucleinopathies which is being approached using both small molecule compounds and ASYN-targeted biologics. Minzasolmin (UCB0599) is an orally bioavailable and brain-penetrant small molecule ASYN misfolding inhibitor in clinical development as a disease-modifying therapeutic for Parkinson’s disease. Herein the results of preclinical evaluations of minzasolmin that formed the basis for subsequent clinical development are described. Pharmacokinetic evaluations of intraperitoneal 1 and 5 mg/kg minzasolmin in wildtype mice revealed parallel and dose-proportional exposures in brain and plasma. Three-month administration studies in the Line 61 transgenic mouse model of PD were conducted to measure ASYN pathology and other PD-relevant endpoints including markers of CNS inflammation, striatal DAT labeling and gait. Reductions in ASYN pathology were correlated with improved aspects of gait and balance, reductions in CNS inflammation marker abundance, and normalized striatal DAT levels. These findings provide support for human dose determinations and have informed the translational strategy for clinical trial design and biomarker selection for the ongoing clinical studies of minzasolmin in patients living with early-stage Parkinson’s disease (ClinicalTrials.gov ID: NCT04658186; EudraCT Number 2020–003265).

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson's disease.

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson’s disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson’s disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson’s. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson’s and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson’s disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson’s disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson’s disease.

Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson\u2019s disease

Parkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes potentially a trigger initiating α-syn misfolding. However, the effects α-syn alterations on the gut virome have not been investigated. In this study, we show longitudinal faecal virome changes in rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn, with alterations compounded by the addition of LPS. Changes in rat faecal viromes were observed after one month and did not resolve within the study’s five-month observational period. These results suggest that virome alterations may be reactive to host α-syn changes that are associated with PD development.

Precision medicine to identify optimal diagnostic and therapeutic interventions for Parkinson's Disease

Objective: Parkinson's disease, the second most common neurodegenerative disorder afflicting 10 million people worldwide and the fourteenth leading cause of death in the United States, is caused by the death of dopaminergic neurons that regulate movement in the substantia nigra pars compacta. Mechanisms contributing to the development of Parkinson’s disease in vulnerable individuals include protein misfolding, protein aggregation, and mitochondrial dysfunction. In order to develop guidelines for clinicians to utilize precision medicine to develop treatment plans to address the specific needs of individuals with Parkinson’s disease and related conditions, we have developed algorithms for diagnosis and treatment based on their view of available knowledge. We reviewed the key literature on the pathogenesis of Parkinson’s disease on PubMed and google scholar in order to propose guidelines for the development of diagnostic and therapeutic interventions for people with Parkinson’s disease and related conditions. In about 25 percent of patients, clinicians incorrectly diagnose Parkinson’s disease. Causes of misdiagnosis include a lack of algorithms and inadequate use of diagnostic modalities. Four main mechanisms that may contribute to the development of Parkinson's disease (misfolding of alpha-synuclein, mitochondrial dysfunction, dysfunctional ubiquitin proteasomal pathways, and abnormal autophagy) and different diagnostic modalities (structured interview and examination, laboratory assessments, neuropathology, genetic testing, neuroimaging) will form the basis for our algorithm for the diagnosis and treatment of Parkinson’s disease and related conditions. Clinicians, administrators, policy planners, advocates, and other concerned individuals will benefit from the adoption of our guidelines for the diagnosis and treatment of Parkinson’s disease and related conditions.

Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease.

Altered conformation of α-synuclein drives dysfunction of synaptic vesicles in a synaptosomal model of Parkinson's disease.

Serum and Fecal Markers of Intestinal Inflammation and Intestinal Barrier Permeability Are Elevated in Parkinson’s Disease

Parkinson’s disease (PD) is characterized by alpha-synuclein misfolding with subsequent intraneuronal amyloid formation and accumulation, low grade neuroinflammatory changes, and selective neurodegeneration. Available evidence suggests that the pathology usually begins in the gut and olfactory mucosa, spreading to the brain via the vagus and olfactory nerves, by a prion-like mechanism. A causal relationship has not been established, but gut dysbiosis is prevalent in PD and may lead to intestinal inflammation and barrier dysfunction. Additionally, epidemiological data indicate a link between inflammatory bowel diseases and PD. Calprotectin and zonulin are markers of intestinal inflammation and barrier permeability, respectively. We evaluated their serum and fecal levels in 22 patients with sporadic PD and 16 unmatched healthy controls. Mean calprotectin was higher in PD, both in serum (14.26 mcg/ml ± 4.50 vs. 5.94 mcg/ml ± 3.80, p = 0.0125) and stool (164.54 mcg/g ± 54.19 vs. 56.19 mcg/g ± 35.88, p = 0.0048). Mean zonulin was also higher in PD serum (26.69 ng/ml ± 3.55 vs. 19.43 ng/ml ± 2.56, p = 0.0046) and stool (100.19 ng/ml ± 28.25 vs. 37.3 ng/ml ± 13.26, p = 0.0012). Calprotectin was above the upper reference limit in 19 PD serums and 6 controls (OR = 10.56, 95% CI = 2.17–51.42, p = 0.0025) and in 20 PD stool samples and 4 controls (OR = 30, 95% CI = 4.75–189.30, p = 0.000045). Increased zonulin was found only in the stool samples of 8 PD patients. Despite the small sample size, our findings are robust, complementing and supporting other recently published results. The relation between serum and fecal calprotectin and zonulin levels and sporadic PD warrants further investigation in larger cohorts.

In Silico and In Vitro Validation of Equine Alpha‐synuclein Misfolding Relevant to Pituitary Pars Intermedia Dysfunction

Alpha-synuclein is an abundant neuronal protein composed of 140 amino acids. Compelling evidence suggests that alpha-synuclein can acquire a neurotoxic feature that kills dopamine secreting nerve cells in horses afflicted with Cushing's disease (known as pituitary pars intermedia dysfunction, PPID). Using bioinformatic analysis, we have identified that equine alpha-synuclein has a high propensity to convert (misfold and aggregate) into this toxic form. While alpha-synuclein is thought to play a pathogenic role in horses with equine PPID, it is unclear how alpha-synuclein aggregates. We hypothesize that specific region(s) and/or amino acid variation(s) in equine alpha-synuclein contribute to its misfolding. To test this hypothesis, we designed a bank of fragmented peptides to identify the region(s) most prone to aggregation. Bioinformatic analysis of equine alpha-synuclein with Tango program indicated a similar propensity to aggregate as human alpha-synuclein (Fig. 1). Region 62-87 of the equine alpha-synuclein peptide is the region most prone to aggregation according to Thioflavin T fluorescence assay. This fragment peptide 62-87 is capable of generating mature fibrils as validated by electron microscopy. The discovery of the region responsible for equine alpha-synuclein misfolding is relevant for the development of pharmacological agents that block the formation of alpha-synuclein toxic aggregates.

Экзосомы плазмы крови при наследственных формах болезни Паркинсона

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. The prion properties of alpha-synuclein are still under discussion. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The most frequent inherited forms of the disease are PD associated with mutation in the leucine-rich repeat kinase 2 (LRRK2-PD) and glucocerebrosidase (GBA-PD) genes. The aim of our work is to evaluate the concentration and size of exosomes derived from blood plasma of patients with GBA-PD, asymptomatic GBA mutation carriers, and the effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. Plasma extracellular vesicles were isolated via chemical precipitation and sequential ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis (NTA), and flow cytometry. Total alpha-synuclein level in plasma exosomes was estimated by enzyme-linked immunosorbent assay. Patients with sporadic PD, PD with dementia, patients with inherited PD (GBA-PD, LRRK2-PD), and GBA mutation carriers were included in the study. The concentration on plasma exosomes was higher in GBA-PD patients that in sporadic PD patients, asymptomatic carriers of mutations on GBA gene, and control (p = 0.004, 0.019 and 0.0001 respectively). The size of plasma exosomes was higher in GBA-PD patients compared to asymptomatic carriers of GBA mutations and control (p = 0.009 and 0.0001, respectively). No significant difference was found for exosomal alpha-synuclein levels in the studied groups. Our results allowed us to suggest that a decrease in GBA activity may affect the pool of plasma exosomes, and mutations in the LRRK2 and GBA genes do not influence the level of plasma exosomal alpha-synuclein.

Functional Modulators of Resilience to Age-Associated Dopaminergic Neurodegeneration in C. elegans

The societal costs of neurodegenerative diseases demand a sense of urgency and innovative strategies toward therapeutic intervention. We have exploited the experimental attributes of roundworm, C. elegans, as a model to expedite discovery of genetic and chemical modifiers of the age-dependent progressive neurodegeneration of dopaminergic neurons commonly associated with Parkinson’s disease (PD). Our model of transgenic nematodes overexpressing the misfolding-prone familial PD gene product, alpha-synuclein, has proven prescient in illuminating key aspects of PD pathology, including vesicular trafficking, autophagy, stress response, lipid dynamics, as well as the first evidence of endolysosomal function in effecting dopaminergic neurodegeneration. Subsequent chemical-genetic analyses reveal a mechanism whereby dopamine transport intersects with epigenetic control of gene expression through proteins functioning in endocytic regulation to modulate neuroprotection. We theorize this reflects a “tunable” nexus of gene-by-environmental regulation where dopamine levels, which impact alpha-synuclein misfolding, are coordinately controlled with epigenetic response to mediate resilience to age-dependent neurodegeneration.

Oral administration of squalamine protects rats from parkinsonism

Oral administration of squalamine protects rats from parkinsonism

Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration.

With idiopathic Parkinson's disease being a common entity, parkinsonism in acquired hepatocerebral degeneration (AHD) in the context of Manganese (Mn) has gained importance in recent years. An insight into the pathomechanisms behind this disease has been put forth. How can Mn as a divalent metal exert its effect in leading to chronic neurodegenerative disorder? Secondary to decreased excretion in liver cirrhosis, Mn significantly alters the striatal dopaminergic system. Management of this debilitating disease also focuses on different aspects where Mn has been involved in the pathogenesis. We have put forth the details behind Mn effects in Parkinson’s, which will be a guide for better understanding and management of this disease.A literature search was performed using PubMed as a sole database, and all the articles were peer-reviewed. The author tried to follow the PRISMA guidelines. Inclusion criteria were set for 10 years, with most studies with in the last seven years. All types of study designs were included relevant to the topic, clearly delineating the pathomechanisms of Mn in the disease and also its management. After extensive research, through the PubMed database, we found that Parkinson's disease is one of the neurological complications in advanced liver cirrhosis. Mn is an essential element behind its pathogenesis; it works at different cellular levels to promote neurotoxicity. From its influx to its effects on dopamine transporters (DAT), where it disrupts dopamine homeostasis also altering postsynaptic dopamine (D2) receptors, it disrupts mitochondria and the endoplasmic reticulum (ER) promotes oxidative stress and neuroinflammation. Misfolding of alpha-synuclein (α-Syn) is promoted on chronic exposure to Mn where α-Syn from being neuroprotective becomes neurotoxic. It also alters glutaminergic and gabaergic neurotransmission. In a nutshell, the diversity of its effect on nigrostriatal denervation is challenging. The importance of neuroimaging and various approaches to management is also discussed. AHD, an uncommon entity in advanced liver cirrhosis, needs more awareness so that it can be diagnosed earlier and better therapeutic options can be sought. Our study highlighted Mn mechanisms behind this clinical entity, putting forth grounds for a better understanding of this disease. Advanced research targeting Mn for managing this disease will be revolutionary.

Using CRISPR-X for Optimization of Antibodies Towards A30P α-synuclein Oligomers in Immunotherapy of Parkinson’s Disease

Introduction: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive cell death in the substantia nigra portion of the midbrain, which results in severe dopamine imbalance and a subsequent loss of refined motor control. Pathogenicity arises from mutations driving the misfolding of alpha synuclein (ɑ-syn), thus leading to oligomerization and formation of Lewy body aggregates in neurons. Previous research has identified the A30P mutated oligomers, which are connected to familial early-onset PD, as particularly toxic intermediates. However, there are insufficient methods of targeting them in isolation of other forms of the ɑ-syn protein. We aim to modify existing approaches to immunotherapy of PD, by use of CRISPR-X and phage display, to design antibodies that are highly specific to the A30P oligomer. Methods: We will use CRISPR-X to produce a diverse library of antibodies by introducing point mutations in the sequences encoding their variable light (VL) and heavy (VH) chains. Then, via insertion into bacteriophages for multiple rounds of phage display selection, we should obtain a polyclonal selection of antibodies that exclusively recognize epitopes on A30P ɑ-syn. Each variant then produces a distinct monoclonal phage colony to be incubated with relevant antigens for affinity testing via enzyme-linked immunosorbent assay (ELISA). Expected Results: We expect that measurements from ELISA would indicate low dissociation constants (KD) within the low micromolar (10-6) to nanomolar (10-7 to 10-9) range, when incubated with A30P oligomers. We predict that the resultant antibodies would have a higher affinity for the A30P oligomeric ɑ-syn than other forms of the protein. Furthermore, the novel antibodies are expected to have a higher specificity to this target antigen than the original antibodies that were modified. Discussion: By determining binding affinity, we verify the effectiveness of this method for improving specificity of in vitro antibody design. Upon further investigation using mice models, we would anticipate these novel antibodies could produce a specific reversal of the toxic effects of A30P in neuronal tissue. Conclusion: This study aims to establish a potential for CRISPR-X and phage selection to be used in antibody optimization for developing an immunotherapeutic treatment for PD.

1148 Conceiving A Connected, Preventative Treatment Stance Across The Brain-gut-microbiota Axis In Prodromal Parkinson’s Disease: The Power Of Preventative Sleep Health

Abstract Introduction Early non-motor symptoms of Parkinson’s Disease (PD) include sleep and digestive disturbances that share a common pathology via alpha-synuclein (AS) deposition in the central nervous system (CNS) and formation in the enteric (ENS). The concept of prodromal PD as expressed by the brain-gut-microbiota axis continues to gain credibility across multiple literatures; yet, no unified treatment plan has been suggested. Disconnected, symptomatic treatment of prodromal PD may unintentionally hasten its development via compromise of REM sleep quality and reciprocal gut health. A more connected, comprehensive approach is needed. We conducted a systematic literature review to hypothesize next steps in treatment research for prodromal PD. Methods A systematic literature review using the Boolean combinations of “ALPHA-SYNUCLEIN” & - “SLEEP”, “GUT MICROBIOME”, and “EXERCISE” in all fields, restricted to the last 5 years, focusing on specification of prodromal PD, was conducted. Results were combined with an examination of current treatment practices in PD. Results 38 articles met inclusion criteria. Results were categorized through a presupposed primacy of sleep. Conclusion Due to the emerging nature of the prodromal PD idea, current treatment practice is myopic and may contribute to the progression of PD. Specifically, 1) sedative-hypnotic sleep interventions suppress REM, where clearing of CNS alpha-synuclein occurs, and 2) proton-pump inhibitors (PPI) cause significant gut dysbiosis, which may contribute to initial AS misfolding in the gut. Early identification of prodromal PD symptoms via cross-referenced clinical interview may allow for early behavioral interventions that underlie healthy brain-gut-microbiota axis functioning. Results outline specific measures that may slow PD-related synucleinopothies. The highest impact practices in this regard are REM-focused sleep hygiene and cardiovascular conditioning in a reciprocal relationship, highlighting the necessity of an early-intervention, preventative health model for conquering PD. Support This work was made possible in part by a donation from Drs. Shane Pitts and Michelle Hilgeman in support of Birmingham-Southern College’s Southern Sleep Laboratory.

Альфа-синуклеин экзосом плазмы крови при наследственных формах болезни Паркинсона

Предполагается, что экзосомы (микровезикулы размером 40-100 нм) могут играть ключевую роль в транспорте патогенных форм альфа-синуклеина при болезни Паркинсона (БП). В настоящем исследовании проведена оценка влияния мутаций в генах GBA и LRRK2 на уровень альфа-синуклеина экзосом плазмы крови. Показано, что мутации в генах GBA и LRRK2 не влияют на уровень альфа-синуклеина экзосом плазмы крови. Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder. Alpha-synuclein misfolding and aggregation resulting in neurototoxicity is a hallmark of PD. Exosomes (extrcellular vesicles 40-100 nm in size) can play a key role in the transport of pathogenic forms of alpha-synuclein. The aim of our work is to evaluate an effect of GBA and LRRK2 mutations on alpha-synuclein level in exosomes derived from peripheral blood plasma. No significant difference was found for exosomal alpha-synuclein levels patients with sporadic, GBA- and LRRK2- associated PD, PD with dementia compared to controls. Our results indicate that mutations in the LRRK2 and GBA genes do not influence on plasma exosomal alpha-synuclein level.

The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson\u2019s disease

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.