Human Parkinson's Disease Research Articles

α-Phellandrene: A Promising Natural Remedy for Rotenone-Induced Parkinson's Disease.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the pro-gressive loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms. Current treatments primarily offer symptomatic relief without halt-ing disease progression. This has driven the exploration of natural compounds with neuropro-tective properties. In previous studies, α-phellandrene, a monoterpene present in essential oils of various aromatic plants, has shown promise in mitigating neurodegenerative processes. This study focuses on alpha-phellandrene's therapeutic potential in a rotenone-induced Parkinson's Disease model. Rotenone, a mitochondrial complex I inhibitor, is commonly used to induce PD-like symptoms in experimental models due to its ability to mimic the neurodegenerative processes observed in human PD. Our review explores the neuroprotective effects of alpha-phellandrene, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic properties. Experimental groups of rodents received rotenone to induce PD-like symptoms, followed by alpha-phellandrene treatment. Biochemical analyses were performed to measure oxidative stress markers, inflammatory cytokines, and apoptotic signals in brain tissues. Results indi-cated that alpha-phellandrene administration significantly improved motor function and re-duced rotenone-induced oxidative stress, inflammation, and apoptosis in dopaminergic neu-rons. Histopathological examinations revealed a notable preservation of neuronal integrity in alpha-phellandrene-treated groups compared to controls. In conclusion, alpha-phellandrene demonstrates considerable neuroprotective effects in a rotenone-induced Parkinson's dmodel. These findings suggest that alpha-phellandrene could be a promising natural therapeutic agent for PD, warranting further investigation into its mechanisms of action and potential clinical applications. Specifically, our review indicates that alpha-phellandrene may exert neuropro-tective effects by various mechanisms, such as reducing oxidative stress, modulating neuro-transmitter levels, or inhibiting neuroinflammation. These mechanisms highlight its potential to alleviate PD symptoms and slow disease progression, underscoring the need for in-depth studies to validate these therapeutic effects in clinical settings.

Coronin1A regulates the trafficking of alpha synuclein in microglia.

Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an Nlrp3-dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not Nlrp3-dependent in αsyn PFF exposure conditions. Coro1A-/- microglia exposed to αsyn PFFs trafficked more αsyn to lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF driven lysosomal stress resulting from Coro1a loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin associated 55kD PARP cleavage product. Post-mortem analysis of the PD mesencephalon supported a role for Coro1a in microglia, revealing elevated levels of Coro1A protein in human PD brains compared to those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that Coro1a protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise.Significance Statement Microglia are responsible for clearing toxic protein aggregates such as alpha synuclein (αsyn) in Parkinson's Disease (PD). PD is slowly progressive, implying that microglia are under proteinaceous stress for an extended time, maintaining some level of homeostasis while attempting to clear pathologically aggregated proteins. Pathological proteins can overload the lysosomes resulting in rupture, decreasing the ability of microglia to clear protein aggregates, and contributing to a hyperreactive inflammatory state. We determined that the protein Coronin1A functions in microglia to attenuate αsyn-induced lysosomal stress, preventing Nlrp3-inflammasome activation, and cell death. These findings identify a protective cellular mechanism operating in microglia that may contribute to the distribution of pathological proteins into the microenvironment.

14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity.

Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein with chaperone-like activity that regulates αsyn folding. 14-3-3θ overexpression reduces αsyn aggregation, transmission between cells, and neuronal loss, while 14-3-3 inhibition promotes αsyn pathology. We previously observed increased 14-3-3θ phosphorylation at serine 232 in human PD and DLB brains. Here we examine 14-3-3θ phosphorylation's effects on αsyn aggregation and toxicity. Using a paracrine αsyn model, we found that the non-phosphorylatable S232A 14-3-3θ protected while the phosphomimetic S232D 14-3-3θ failed to protect against αsyn paracrine toxicity. The S232A mutant reduced oligomerization of released αsyn while the S232D mutant did not. The S232D mutant showed significant reduction in αsyn binding compared to wildtype or S232A 14-3-3θ. Using knock-in mouse models expressing the S232A or S232D mutation in the cortex and hippocampus, we examined the impact of S232 phosphorylation on αsyn aggregation in the αsyn preformed fibril (PFF) model. Primary neurons from S232D mice showed increased αsyn inclusion formation compared to neurons from Cre control mice upon PFF treatment. In contrast, neurons from S232A mice showed reduced αsyn inclusions. αSyn PFF injection into the dorsolateral striatum induced higher αsyn inclusion numbers in the sensorimotor cortex of S232D mice compared to Cre control mice. In conclusion, 14-3-3θ phosphorylation at S232 interrupts the ability of 14-3-3θ to bind and regulate αsyn aggregation. Increased 14-3-3θ phosphorylation observed in human PD and DLB likely accelerates neurodegeneration in these disorders.

Substantia nigra alterations in mice modeling Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative pathology of the central nervous system. The well-known abnormalities characteristic of PD are dysfunctions in the nigrostriatal system including the substantia nigra of the midbrain and the striatum. Moreover, in PD persons, alpha-synucleinopathy is associated with abnormalities in the dopaminergic brain system. To study the mechanisms of this pathology, genetic models in mice have been designed. Transgenic mice of the B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J strain (referred to as B6.Cg-Tg further in the text) possess the A53T mutation in the human alpha-synuclein SNCA gene. The density of neurons in the prefrontal cortex, hippocampus, substantia nigra and striatum in B6.Cg-Tg mice was assessed in our previous work, but the dopaminergic system was not studied there, although it plays a key role in the development of PD. The aim of the current study was to investigate motor coordination and body balance, as well as dopaminergic neuronal density and alpha-synuclein accumulation in the substantia nigra in male B6.Cg-Tg mice at the age of six months. Wild-type mice of the same sex and age, siblings of the B6.Cg-Tg mice from the same litters, lacking the SNCA gene with the A53T mutation, but expressing murine alpha-synuclein, were used as controls (referred to as the wild type further in the text). Motor coordination and body balance were assessed with the rota-rod test; the density of dopaminergic neurons and accumulation of alpha-synuclein in the substantia nigra were evaluated by the immunohistochemical method. There was no difference between B6.Cg-Tg mice and WT siblings in motor coordination and body balance. However, accumulation of alpha-synuclein and a decrease in the number of dopaminergic neurons in the substantia nigra were found in the B6.Cg-Tg mouse strain. Thus, the mice of the B6.Cg-Tg strain at the age of six months have some symptoms of the onset of PD, such as the accumulation of mutant alpha-synuclein and a decrease in the number of dopaminergic neurons in the substantia nigra. Taken together, the results obtained in our work qualify the B6.Cg-Tg strain as a pertinent model for studying the early stage of human PD already at the age of six months.

Templating of Monomeric Alpha-Synuclein Induces Inflammation and SNpc Dopamine Neuron Death in a Genetic Mouse Model of Synucleinopathy.

While the etiology of most cases of Parkinson's disease (PD) are idiopathic, it has been estimated that 5-10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HC, HPLC, and cytokine analysis, we examined the sequelae of intraparenchymal brain seeding of pre-formed fibrils (PFFs) and monomeric α-syn in C57BL/6J (WT) and A53T SNCA mutant mice. We found that injection of PFFs, but not monomeric α-syn, into the striatum of C57BL/6J mice induced spread of aggregated α-syn, loss of SNpc DA neurons and increased neuroinflammation. However, in A53T SNCA mice, we found that both PFFs and monomeric α-syn induced this pathology. This suggests that the conformation changes in α-syn seen in the A53T strain can recruit wild-type α-syn to a pathological misfolded conformation which may provide a mechanism for the induction of PD in humans with SNCA duplication/triplication.

The utilization of CRISPR-Cas9 with human pluripotent stem cell for Parkinson's disease modeling

Abstract. Parkinson's disease (PD), also often referred to as "parkinsonism," is a neurodegenerative disorder. Those afflicted with this condition are frequently elderly, which results in a considerable decline in their quality of life and overall well-being. Although there are major breakthroughs in PD research, there remains an incomplete grasp of the disease's pathogenesis and the formulation of innovative treatment approaches. This has led to an urgent need for a technology that can recapitulate all the features of human PD. The emergence of induced pluripotent stem cells (iPSC) coupled with the rising appeal of Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9 (CRISPR-Cas9) technology, the construction of PD models through the combination of iPSC and CRISPR-Cas9 has emerged as a crucial area of research in the field of PD. Employing patients' somatic cells, transformed into iPSC and integrated with CRISPR-Cas9 for genetic modification, has facilitated the duplication of the genetic makeup of neural cells associated with PD, thereby facilitating the investigation of the influence of diverse genotypes on disease progression and treatment response. This review outlines the application and future development of iPSC and CRISPR-Cas9 technologies for the study of Parkinson's disease pathogenesis. The technology enables scientists to gain a deeper understanding of PD and paves the way for the development of novel therapeutic approaches in the future.

α-synuclein overexpression and the microbiome shape the gut and brain metabolome in mice

Pathological forms of α-synuclein contribute to synucleinopathies, including Parkinson’s disease (PD). Most cases of PD arise from gene-environment interactions. Microbiome composition is altered in PD, and gut bacteria are causal to symptoms in animal models. We quantitatively profiled nearly 630 metabolites in the gut, plasma, and brain of α-synuclein-overexpressing (ASO) mice, compared to wild-type (WT) animals, and comparing germ-free (GF) to specific pathogen-free (SPF) animals (n = 5 WT-SPF; n = 6 ASO-SPF; n = 6 WT-GF; n = 6 ASO-GF). Many differentially expressed metabolites in ASO mice are also dysregulated in human PD patients, including amine oxides, bile acids and indoles. The microbial metabolite trimethylamine N-oxide (TMAO) strongly correlates from the gut to the plasma to the brain in mice, notable since TMAO is elevated in the blood and cerebrospinal fluid of PD patients. These findings uncover broad metabolomic changes that are influenced by the intersection of host genetics and microbiome in a mouse model of PD.

Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Aging is the biggest risk factor for Parkinson's disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss, and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons without generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age. Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress, and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity. These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in the idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in the human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.

14-3-3 phosphorylation inhibits 14-3-3θ's ability to regulate LRRK2 kinase activity and toxicity.

LRRK2 mutations are among the most common genetic causes for Parkinson's disease (PD), and toxicity is associated with increased kinase activity. 14-3-3 proteins are key interactors that regulate LRRK2 kinase activity. Phosphorylation of the 14-3-3θ isoform at S232 is dramatically increased in human PD brains. Here we investigate the impact of 14-3-3θ phosphorylation on its ability to regulate LRRK2 kinase activity. Both wildtype and the non-phosphorylatable S232A 14-3-3θ mutant reduced the kinase activity of wildtype and G2019S LRRK2, whereas the phosphomimetic S232D 14-3-3θ mutant had minimal effects on LRRK2 kinase activity, as determined by measuring autophosphorylation at S1292 and T1503 and Rab10 phosphorylation. However, wildtype and both 14-3-3θ mutants similarly reduced the kinase activity of the R1441G LRRK2 mutant. 14-3-3θ phosphorylation did not promote global dissociation with LRRK2, as determined by co-immunoprecipitation and proximal ligation assays. 14-3-3s interact with LRRK2 at several phosphorylated serine/threonine sites, including T2524 in the C-terminal helix, which can fold back to regulate the kinase domain. Interaction between 14-3-3θ and phosphorylated T2524 LRRK2 was important for 14-3-3θ's ability to regulate kinase activity, as wildtype and S232A 14-3-3θ failed to reduce the kinase activity of G2019S/T2524A LRRK2. Finally, we found that the S232D mutation failed to protect against G2019S LRRK2-induced neurite shortening in primary cultures, while the S232A mutation was protective. We conclude that 14-3-3θ phosphorylation destabilizes the interaction of 14-3-3θ with LRRK2 at T2524, which consequently promotes LRRK2 kinase activity and toxicity.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated adult zebrafish as a model for Parkinson’s Disease

Dopamine (DA) is a catecholamine neurotransmitter that works to regulate cognitive functions. Patients affected by Parkinson’s Disease (PD) experience a loss of dopaminergic neurons and downregulated neural DA production. This leads to cognitive and physical decline that is the hallmark of PD for which no cure currently exists. Danio rerio, or zebrafish, have become an increasingly popular disease model used in PD pharmaceutical development. This model still requires extensive development to better characterize which PD features are adequately represented. Furthermore, the great majority of PD zebrafish models have been performed in embryos, which may not be relevant towards age-related human PD. As an improvement, mature D. rerio were treated with neurotoxic prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through intraperitoneal injection to induce parkinsonism. Behavioral analysis confirmed disparities in movement between saline-injected control and the MPTP-injected experimental group, with swim distance and speed significantly lowered seven days after MPTP injection. Simultaneously, cognitive decline was apparent in MPTP-injected zebrafish, demonstrated by decreased alternation in a y-maze. RT-qPCR confirmed trends consistent with downregulation in Parkinsonian genetic markers, specifically DA transporter (DAT), MAO-B, PINK1. In summary, mature zebrafish injected with MPTP present with similar movement and cognitive decline as compared to human disease. Despite its benefits, this model does not appear to recapitulate pathophysiology of the disease with the full profile of expected gene downregulation. Because of this, it is important that researchers looking for pharmacological interventions for PD only use this zebrafish model when targeting the human-relevant PD symptoms and causes that are represented.

Unveiling Lobophytum sp. the neuroprotective potential of Parkinson's disease through multifaceted mechanisms, supported by metabolomic analysis and network pharmacology

A main feature of neurodegenerative diseases is the loss of neurons. One of the most prevalent neurodegenerative illnesses is Parkinson disease (PD). Although several medications are already approved to treat neurodegenerative disorders, most of them only address associated symptoms. The main aim of the current study was to examine the neuroprotective efficacy and underlying mechanism of Lobophytum sp. crude extract in a rotenone-induced rat model of neurodegeneration mimicking PD in humans. The influence of the treatment on antioxidant, inflammatory, and apoptotic markers was assessed in addition to the investigation of TH (tyrosine hydroxylase) immunochemistry, histopathological changes, and α-synuclein. Metabolomic profiling of Lobophytum sp. crude extract was done by using High-Resolution Liquid Chromatography coupled with Mass Spectrometry (HR-LC–ESI–MS), which revealed the presence of 20 compounds (1–20) belonging to several classes of secondary metabolites including diterpenoids, sesquiterpenoids, steroids, and steroid glycosides. From our experimental results, we report that Lobophytum sp. extract conferred neuroprotection against rotenone-induced PD by inhibiting ROS formation, apoptosis, and inflammatory mediators including IL-6, IL-1β, and TNF-α, NF-кB, and subsequent neurodegeneration as evidenced by decreased α-synuclein deposition and enhanced tyrosine hydroxylase immunoreactivity. Moreover, a computational network pharmacology study was performed for the dereplicated compounds from Lobophytum sp. using PubChem, SwissTarget Prediction, STRING, DisGeNET, and ShinyGO databases. Among the studied genes, CYP19A1 was the top gene related to Parkinson’s disease. Dendrinolide compounds annotated a high number of parkinsonism genes. The vascular endothelial growth factor (VEGF) pathway was the top signaling pathway related to the studied genes. Therefore, we speculate that Lobophytum sp. extract, owing to its pleiotropic mechanisms, could be further developed as a possible therapeutic drug for treating Parkinson's disease.

Targeting ferroptosis with the lipoxygenase inhibitor PTC-041 as a therapeutic strategy for the treatment of Parkinson's disease.

Parkinson's disease is the second most common neurodegenerative disorder, affecting nearly 10 million people worldwide. Ferroptosis, a recently identified form of regulated cell death characterized by 15-lipoxygenase-mediated hydroperoxidation of membrane lipids, has been implicated in neurodegenerative disorders including amyotrophic lateral sclerosis and Parkinson's disease. Pharmacological inhibition of 15 -lipoxygenase to prevent iron- and lipid peroxidation-associated ferroptotic cell death is a rational strategy for the treatment of Parkinson's disease. We report here the characterization of PTC-041 as an anti-ferroptotic reductive lipoxygenase inhibitor developed for the treatment of Parkinson's disease. In these studies, PTC-041 potently protects primary human Parkinson's disease patient-derived fibroblasts from lipid peroxidation and subsequent ferroptotic cell death and prevents ferroptosis-related neuronal loss and astrogliosis in primary rat neuronal cultures. Additionally, PTC-041 prevents ferroptotic-mediated α-synuclein protein aggregation and nitrosylation in vitro, suggesting a potential role for anti-ferroptotic lipoxygenase inhibitors in mitigating pathogenic aspects of synucleinopathies such as Parkinson's disease. We further found that PTC-041 protects against synucleinopathy in vivo, demonstrating that PTC-041 treatment of Line 61 transgenic mice protects against α-synuclein aggregation and phosphorylation as well as prevents associated neuronal and non-neuronal cell death. Finally, we show that. PTC-041 protects against 6-hydroxydopamine-induced motor deficits in a hemiparkinsonian rat model, further validating the potential therapeutic benefits of lipoxygenase inhibitors in the treatment of Parkinson's disease.

Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

Construct, Face, and Predictive Validity of Parkinson's Disease Rodent Models.

Parkinson's disease (PD) is the second most common neurodegenerative disease globally. Current drugs only alleviate symptoms without halting disease progression, making rodent models essential for researching new therapies and understanding the disease better. However, selecting the right model is challenging due to the numerous models and protocols available. Key factors in model selection include construct, face, and predictive validity. Construct validity ensures the model replicates pathological changes seen in human PD, focusing on dopaminergic neurodegeneration and a-synuclein aggregation. Face validity ensures the model's symptoms mirror those in humans, primarily reproducing motor and non-motor symptoms. Predictive validity assesses if treatment responses in animals will reflect those in humans, typically involving classical pharmacotherapies and surgical procedures. This review highlights the primary characteristics of PD and how these characteristics are validated experimentally according to the three criteria. Additionally, it serves as a valuable tool for researchers in selecting the most appropriate animal model based on established validation criteria.

Mitochondrial stress-induced H4K12 hyperacetylation dysregulates transcription in Parkinson's disease.

Aberrant epigenetic modification has been implicated in the pathogenesis of Parkinson's disease (PD), which is characterized by the irreversible loss of dopaminergic (DAergic) neurons. However, the mechanistic landscape of histone acetylation (ac) in PD has yet to be fully explored. Herein, we mapped the proteomic acetylation profiling changes at core histones H4 and thus identified H4K12ac as a key epigenomic mark in dopaminergic neuronal cells as well as in MitoPark animal model of PD. Notably, the significantly elevated H4K12ac deposition in post-mortem PD brains highlights its clinical relevance to human PD. Increased histone acetyltransferase (HAT) activity and decreased histone deacetylase 2 (HDAC2) and HDAC4 were found in experimental PD cell models, suggesting the HAT/HDAC imbalance associated with mitochondrial stress. Following our delineation of the proteasome dysfunction that possibly contributes to H4K12ac deposition, we characterized the altered transcriptional profile and disease-associated pathways in the MitoPark mouse model of PD. Our study uncovers the axis of mitochondrial impairment-H4K12ac deposition-altered transcription/disease pathways as a neuroepigenetic mechanism underlying PD pathogenesis. These findings provide mechanistic information for the development of potential pharmacoepigenomic translational strategies for PD.

A review of MPTP-induced parkinsonism in adult zebrafish to explore pharmacological interventions for human Parkinson's disease.

Novel work in adult zebrafish, Danio rerio, to recapitulate human neurodegenerative disease has proven useful in both pharmaceutical development and research on genetic disease. Due to high genetic homology to humans, affordable husbandry, relatively quick life cycle breeding times, and robust embryo production, zebrafish offer a promising model to test pharmaceutical performance in a high throughput, in vivo setting. Currently, most research in zebrafish models of Parkinson's disease induces the disease in larval or embryonic stage organisms due to ease of administration, with advancement through developmental stages taking only a matter of days. The use of early-stage organisms limits the usability of zebrafish as models for adult disease and specifically age-related neurodegenerative conditions. Recently, researchers have sought to extend the usability of zebrafish into models for Parkinson's disease. Specifically, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has emerged as a prodrug that upon injection well-encompasses the biochemical mechanisms and symptomology associated with Parkinson's disease. By utilizing MPTP in an adult zebrafish model, advancements in Parkinson's disease research may be achieved. This paper highlights the recent research on this model, comparing it to the human form of Parkinson's disease.

GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder

Sleep disturbances, including rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness, and insomnia, are common non-motor manifestations of Parkinson’s disease (PD). Little is known about the underlying mechanisms, partly due to the inability of current rodent models to adequately mimic the human PD sleep phenotype. Clinically, increasing studies have reported that variants of the glucocerebrosidase gene (GBA) increase the risk of PD. Here, we developed a mouse model characterized by sleep–wakefulness by injecting α-synuclein preformed fibronectin (PFF) into the sublaterodorsal tegmental nucleus (SLD) of GBA L444P mutant mice and investigated the role of the GBA L444P variant in the transition from rapid eye movement sleep behavior disorder to PD. Initially, we analyzed spectral correlates of REM and NREM sleep in GBA L444P mutant mice. Importantly, EEG power spectral analysis revealed that GBA L444P mutation mice exhibited reduced delta power during non-rapid eye movement (NREM) sleep and increased theta power (8.2–10 Hz) in active rapid eye movement (REM) sleep phases. Our study revealed that GBA L444P-mutant mice, after receiving PFF injections, exhibited increased sleep fragmentation, significant motor and cognitive dysfunctions, and loss of dopaminergic neurons in the substantia nigra. Furthermore, the over-expression of GBA-AAV partially improved these sleep disturbances and motor and cognitive impairments. In conclusion, we present the initial evidence that the GBA L444P mutant mouse serves as an essential tool in understanding the complex sleep disturbances associated with PD. This model further provides insights into potential therapeutic approaches, particularly concerning α-synuclein accumulation and its subsequent pathological consequences.

Effects of Glyphosate on Cognitive Development, Sensory Sensitivity and Locomotor Balance in Male Rats

Glycophate is the active ingredient in RoundupⓇ hebicide, which is commonly used in agriculture. Exposure to the herbicide glyphosate may affect the development of Parkinson Disease in humans. pre-natal and post-natal exposure to glyphosate exerts neurological effects and neuropsychiatric effects, even at low concentrations. This study aimed to examine the effects on cognitive, sensory and motor development in male rats exposed to the active ingredient glycophate in RoundupⓇ at various concentrations. In this study using test animals in the form of male rats with an age of 10 weeks, then the rats were divided into 4 treatment groups, namely the normal group, 100 µL, 50 µL, and 25 µL RoundupⓇ, induction was given orally every day for 4 weeks. Then at the last week, the body weight of the rats was measured and several tests were conducted to see the effect of glycophate induction on rat cognition through the morris water maze and y maze tests, sensory development through the hot plate test, and rat motor development through the hanging wire test. The results showed that glyphosphate administration affected the body weight of the rats, and affected the cognitive development of the rats. The 50 µL dose treatment group showed the most visible effect of glycophosphate exposure on cognitive tests compared to other groups. In the sensory test, the 50 µL ml dose treatment group also had low sensitivity compared to other groups, and low motor ability compared to other groups. Glycophate was seen to affect the cognitive, sensory and motor development of the rats.

Discovery and Evaluation of Imidazo[2,1-b][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging.

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [125I]ITA-3, with moderate binding affinity (IC50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [125I]ITA-3, we developed a potential PET tracer, [18F]FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC50 = 245 nM), good brain uptake (SUVpeak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [18F]FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

Ecklonia cava Polyphenols Have a Preventive Effect on Parkinson's Disease through the Activation of the Nrf2-ARE Pathway.

Parkinson's disease (PD) is a degenerative neurological disorder defined by the deterioration and loss of dopamine-producing neurons in the substantia nigra, leading to a range of motor impairments and non-motor symptoms. The underlying mechanism of this neurodegeneration remains unclear. This research examined the neuroprotective properties of Ecklonia cava polyphenols (ECPs) in mitigating neuronal damage induced by rotenone via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. Using human neuroblastoma SH-SY5Y cells and PD model mice, we found that ECP, rich in the antioxidant polyphenol phlorotannin, boosted the gene expression and functionality of the antioxidant enzyme NAD(P)H quinone oxidoreductase-1. ECP also promoted Nrf2 nuclear translocation and increased p62 expression, suggesting that p62 helps sustain Nrf2 activation via a positive feedback loop. The neuroprotective effect of ECP was significantly reduced by Compound C (CC), an AMP-activated protein kinase (AMPK) inhibitor, which also suppressed Nrf2 nuclear translocation. In PD model mice, ECPs improved motor functions impaired by rotenone, as assessed by the pole test and wire-hanging test, and restored intestinal motor function and colon tissue morphology. Additionally, ECPs increased tyrosine hydroxylase expression in the substantia nigra, indicating a protective effect on dopaminergic neurons. These findings suggest that ECP has a preventative effect on PD.