Neurodegeneration Of Dopaminergic Neurons Research Articles

Socijalna kognicija u bolesnika sa Parkinsonovom bolešću i poremećajima kontrole impulsa

Introduction: Parkinson's disease (PD) is a slowly progressive degenerative disease characterized by tremors, rigidity, bradykinesia, and postural instability. The pathogenesis of PD is characterized by neurodegeneration of dopaminergic neurons. The prevalence is 1% in the population over 60 years. Chronic use of antiparkinsonian therapy leads to psychomotor and autonomic complications. Impulse Control Disorders (ICDs) are described as the inability of a person to resist an impulse or aspire to a particular behavior that harms that person or their environment and impairs their daily functioning. Social cognition is the ability to make inferences about another person through the perception of their emotions and current mental state. Aim: In the study, social cognition was examined in patients with Parkinson's disease between those with ICD and those without ICD. Material and methods: The study involved 24 patients diagnosed with Parkinson's disease, of which 13 patients had ICD while 11 patients did not have ICD. Participants were diagnosed and tested at the Clinic of Neurology at the University Clinical Center of Serbia. The used tests are the Reading the Mind in the Eyes Test (RMET) and the Faux-Pas Recognition Test adapted to the Serbian language. Results: By testing the difference between the group of patients with and without ICD, no statistically significant difference was found in terms of age, sex, duration of disease, presence of motor complications, and treatment with levodopa, dopamine agonists, or amantadine. A statistically significant difference was found in the achievements on social cognition tests between patients with PD and healthy controls. Conclusion: A statistically significant difference was found in the achievements on social cognition tests between patients with PD and healthy controls. No statistically significant difference was shown in the achievements on the tests of emotional recognition and tests of the theory of mind between the group of patients who had ICD and those without ICD.

Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease

Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4+ and CD8+ T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.Graphical

Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.

Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.

Restoration of Adult Neurogenesis by Intranasal Administration of Gangliosides GD3 and GM1 in The Olfactory Bulb of A53T Alpha-Synuclein-Expressing Parkinson's-Disease Model Mice.

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting the body and mind of millions of people in the world. As PD progresses, bradykinesia, rigidity, and tremor worsen. These motor symptoms are associated with the neurodegeneration of dopaminergic neurons in the substantia nigra. PD is also associated with non-motor symptoms, including loss of smell (hyposmia), sleep disturbances, depression, anxiety, and cognitive impairment. This broad spectrum of non-motor symptoms is in part due to olfactory and hippocampal dysfunctions. These non-motor functions are suggested to be linked with adult neurogenesis. We have reported that ganglioside GD3 is required to maintain the neural stem cell (NSC) pool in the subventricular zone (SVZ) of the lateral ventricles and the subgranular layer of the dentate gyrus (DG) in the hippocampus. In this study, we used nasal infusion of GD3 to restore impaired neurogenesis in A53T alpha-synuclein-expressing mice (A53T mice). Intriguingly, intranasal GD3 administration rescued the number of bromodeoxyuridine + (BrdU +)/Sox2 + NSCs in the SVZ. Furthermore, the administration of gangliosides GD3 and GM1 increases doublecortin (DCX)-expressing immature neurons in the olfactory bulb, and nasal ganglioside administration recovered the neuronal populations in the periglomerular layer of A53T mice. Given the relevance of decreased ganglioside on olfactory impairment, we discovered that GD3 has an essential role in olfactory functions. Our results demonstrated that intranasal GD3 infusion restored the self-renewal ability of the NSCs, and intranasal GM1 infusion promoted neurogenesis in the adult brain. Using a combination of GD3 and GM1 has the potential to slow down disease progression and rescue dysfunctional neurons in neurodegenerative brains.

Tremor in Parkinson’s Disease: From Pathophysiology to Advanced Therapies

Background:Tremor is one of the most prevalent symptoms in Parkinson’s Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD.Methods:A structured literature search through Embase was conducted using the terms “Parkinson’s Disease” AND “tremor” OR “etiology” OR “management” OR “drug resistance” OR “therapy” OR “rehabilitation” OR “surgery.” After initial screening, eligible articles were selected with a focus on published literature in the last 10 years.Discussion:The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its long-term efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are non-invasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor.

Systemic RNA Interference Defective (SID) genes modulate dopaminergic neurodegeneration in C. elegans.

The fine-tuning of gene expression is critical for all cellular processes; aberrations in this activity can lead to pathology, and conversely, resilience. As their role in coordinating organismal responses to both internal and external factors have increasingly come into focus, small non-coding RNAs have emerged as an essential component to disease etiology. Using Systemic RNA interference Defective (SID) mutants of the nematode Caenorhabditis elegans, deficient in gene silencing, we examined the potential consequences of dysfunctional epigenomic regulation in the context of Parkinson’s disease (PD). Specifically, the loss of either the sid-1 or sid-3 genes, which encode a dsRNA transporter and an endocytic regulatory non-receptor tyrosine kinase, respectively, conferred neuroprotection to dopaminergic (DA) neurons in an established transgenic C. elegans strain wherein overexpression of human α-synuclein (α-syn) from a chromosomally integrated multicopy transgene causes neurodegeneration. We further show that knockout of a specific microRNA, mir-2, attenuates α-syn neurotoxicity; suggesting that the native targets of mir-2-dependent gene silencing represent putative neuroprotective modulators. In support of this, we demonstrated that RNAi knockdown of multiple mir-2 targets enhanced α-syn-induced DA neurodegeneration. Moreover, we demonstrate that mir-2 overexpression originating in the intestine can induce neurodegeneration of DA neurons, an effect that was reversed by pharmacological inhibition of SID-3 activity. Interestingly, sid-1 mutants retained mir-2-induced enhancement of neurodegeneration. Transcriptomic analysis of α-syn animals with and without a sid-1 mutation revealed 27 differentially expressed genes with human orthologs related to a variety of diseases, including PD. Among these was pgp-8, encoding a P-glycoprotein-related ABC transporter. Notably, sid-1; pgp-8 double mutants abolished the neurodegeneration resulting from intestinal mir-2 overexpression. This research positions known regulators of small RNA-dependent gene silencing within a framework that facilitates mechanistic evaluation of epigenetic responses to exogenous and endogenous factors influencing DA neurodegeneration, revealing a path toward new targets for therapeutic intervention of PD.

Pharmacological actions of a novel and highly selective D3 dopamine receptor agonist, ML417, in a rodent model of Parkinson’s disease

Since its first use in treating Parkinson’s disease (PD), L‐DOPA has remained the gold standard of therapy for this disorder, defined by the progressive degeneration of dopaminergic neurons in the CNS leading to profound bradykinesia and tremor. The efficacy of L‐DOPA wanes over time and is associated with increasing side effects, including motor fluctuations and dyskinesias. Several dopaminergic agonists have also been introduced to treat PD, including pramipexole and ropinirole, which exhibit fewer motor side effects but are associated with impulse control disorders such as excessive gambling and hypersexuality. Notably, the dopamine receptor subtype(s) mediating the therapeutic actions and/or side effects in PD therapy remain unknown. However, the preference of pramipexole and ropinirole for the D3 dopamine receptor (D3R) suggests the involvement of this subtype, although these drugs also activate the D2R at therapeutic doses. Importantly, no drug currently employed to treat PD alters the course of the disease and the discovery of neuroprotective agents remain an unmet need in PD therapeutics. Recently, we discovered a novel, potent and highly selective agonist for the D3R, ML417, that is brain penetrant and was found to protect against 6‐OHDA‐induced neurodegeneration of dopaminergic neurons (Moritz et al., J. Med. Chem. 63: 5526, 2020). In the current study, we used ML417 to probe the role of the D3R in a rat model of PD. We initially sought to investigate the role of the D3R in ameliorating bradykinesia in a hemi‐parkinsonian rat model induced by 6‐OHDA infusion into the medial forebrain bundle. Using a validated cylindrical treadmill test of locomotion, doses of ML417 up to 20 mg/kg had no effect on improving impairments in walking as assessed by step counts in the hemi‐parkinsonian rats. In contrast, administration of L‐DOPA (6 mg/kg) significantly improves locomotion in the same model. Further, pretreatment with a D3R‐selective antagonist, SB277011A (30 mg/kg), did not attenuate the effects of L‐DOPA in reducing bradykinesia. These results suggest that the D3R does not mediate the anti‐bradykinetic effects of current PD therapeutics. However, we hypothesize that D3R stimulation may be beneficial for the treatment of L‐DOPA‐induced dyskinesias (LIDs) in PD. To test this, we used a chronic L‐DOPA administration paradigm (12 mg/kg/day for 7 days) to induce dyskinesias in the hemi‐parkinsonian rats. Subsequently, the effects of ML417 and SB277011A were assessed in these animals using an abnormal involuntary movement (AIMs) scoring method. Pretreatment with a single dose of ML417 (20 mg/kg) significantly reduced the intensity and duration of dyskinesias promoted with a single dose of L‐DOPA (6 mg/kg). Further, co‐administration of SB277011A (30 mg/kg) with ML417 attenuated the anti‐dyskinetic effects of ML417, suggesting that the benefit is D3R‐mediated. Overall, this study implies that D3R stimulation has no therapeutic effect on bradykinesia in PD, however, it may be beneficial in treating dyskinesias arising from L‐DOPA therapy.

An endogenous polyunsaturated fatty acid, dihomo‐gamma‐linoleic acid, induces neurodegeneration in C. elegans via ferroptosis

Ferroptosis, an iron‐dependent non‐apoptotic programmed cell death, becomes a novel target and mechanism for age‐associated neurodegenerative diseases. Although several ferroptosis regulatory proteins have been identified, the signaling molecules and the pathways of ferroptosis remain largely unknown. Despite membrane lipid peroxidation being one of the molecular hallmarks of ferroptosis, how polyunsaturated fatty acids (PUFAs) involved in the ferroptosis pathway is understudied. Here, we hypothesize that a specific PUFA and/or its downstream metabolites are lipid mediators of ferroptosis. However, it is challenging to identify by which metabolites regulate ferroptosis and to study the associated mechanism due to many different endogenous PUFAs are presented endogenously and each PUFAs can be metabolized to almost a hundred of metabolites.To take on these challenges, we employed Caenorhabditis elegans (C. elegans) as a novel biological model due to the availability of many genetic and imaging tools, conserved ferroptosis pathways between mammal and C. elegans, and adaptability for high‐throughput whole animal aging study. Using the well‐established fluorescent imaging assay in C. elegans, we showed that treatment of dihomo‐gamma‐linoleic acid (DGLA), but not other PUFAs, induces significant (>40% as compared to control) degeneration in dopaminergic neurons immediately after 1 day of treatment. We also found that treatment of DGLA does not affect other somatic tissues of the C. elegans. Our lipidomic analysis demonstrated that DGLA is well‐absorbed by C. elegans. Besides, our results indicated that DGLA triggers neurodegeneration in dopaminergic neurons, likely through ferroptosis. Using our oxidized lipid metabolites analysis and synthetic chemical probes, we revealed that DGLA likely triggers neurodegeneration viatheir oxidized metabolites. Finally, we will also present the potential ferroptosis signaling pathways triggered by DGLA based on our RNA‐seq experiments.Our results will help us identify novel lipid mediators for ferroptosis, which will lead to a better understanding of the molecular mechanism of ferroptosis. Our findings regarding the neuronal specific effects triggered by DGLA also revive a novel cell‐specific regulatory mechanism of ferroptosis. Lastly, our study will find novel therapeutic targets for either preventative treatment or cure for neurodegenerative diseases.

Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson\u2019s disease

In Parkinson’s disease (PD), neurodegeneration of dopaminergic neurons occurs in the midbrain, specifically targeting the substantia nigra (SN), while leaving the ventral tegmental area (VTA) relatively spared in early phases of the disease. Although the SN and VTA are known to be functionally dissociable in healthy adults, it remains unclear how this dissociation is altered in PD. To examine this issue, we performed a whole-brain analysis to compare functional connectivity in PD to healthy adults using resting-state functional magnetic resonance imaging (rs-fMRI) data compiled from three independent datasets. Our analysis showed that across the sample, the SN had greater connectivity with the precuneus, anterior cingulate gyrus, and areas of the occipital cortex, partially replicating our previous work in healthy young adults. Notably, we also found that, in PD, VTA-right cerebellum connectivity was higher than SN-right cerebellum connectivity, whereas the opposite trend occurred in healthy controls. This double dissociation may reflect a compensatory role of the cerebellum in PD and could provide a potential target for future study and treatment.

Adenosine A1 receptor ligands bind to \u03b1-synuclein: implications for \u03b1-synuclein misfolding and \u03b1-synucleinopathy in Parkinson\u2019s disease

BackgroundAccumulating α-synuclein (α-syn) aggregates in neurons and glial cells are the staples of many synucleinopathy disorders, such as Parkinson’s disease (PD). Since brain adenosine becomes greatly elevated in ageing brains and chronic adenosine A1 receptor (A1R) stimulation leads to neurodegeneration, we determined whether adenosine or A1R receptor ligands mimic the action of known compounds that promote α-syn aggregation (e.g., the amphetamine analogue 2-aminoindan) or inhibit α-syn aggregation (e.g., Rasagiline metabolite 1-aminoindan). In the present study, we determined whether adenosine, A1R receptor agonist N6-Cyclopentyladenosine (CPA) and antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) could directly interact with α-syn to modulate α-syn aggregation and neurodegeneration of dopaminergic neurons in the substantia nigra (SN).MethodsNanopore analysis and molecular docking were used to test the binding properties of CPA and DPCPX with α-syn in vitro. Sprague–Dawley rats were administered with 7-day intraperitoneal injections of the A1R ligands and 1- and 2-aminoindan, and levels of α-syn aggregation and neurodegeneration were examined in the SN pars compacta and hippocampal regions using confocal imaging and Western blotting.ResultsUsing nanopore analysis, we showed that the A1R agonists (CPA and adenosine) interacted with the N-terminus of α-syn, similar to 2-aminoindan, which is expected to promote a “knot” conformation and α-syn misfolding. In contrast, the A1R antagonist DPCPX interacted with the N- and C-termini of α-syn, similar to 1-aminoindan, which is expected to promote a “loop” conformation that prevents α-syn misfolding. Molecular docking studies revealed that adenosine, CPA and 2-aminoindan interacted with the hydrophobic core of α-syn N-terminus, whereas DPCPX and 1-aminoindan showed direct binding to the N- and C-terminal hydrophobic pockets. Confocal imaging and Western blot analyses revealed that chronic treatments with CPA alone or in combination with 2-aminoindan increased α-syn expression/aggregation and neurodegeneration in both SN pars compacta and hippocampus. In contrast, DPCPX and 1-aminoindan attenuated the CPA-induced α-syn expression/aggregation and neurodegeneration in SN and hippocampus.ConclusionsThe results indicate that A1R agonists and drugs promoting a “knot” conformation of α-syn can cause α-synucleinopathy and increase neuronal degeneration, whereas A1R antagonists and drugs promoting a “loop” conformation of α-syn can be harnessed for possible neuroprotective therapies to decrease α-synucleinopathy in PD.

Therapeutic Applications of Induced Pluripotent Stem Cell Use in Parkinson’s Disease Models

Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder resulting from the loss of particular nigrostriatal dopaminergic (DA) neuron projections. Current treatments only address the symptoms of PD and do not work to repair the causative neurodegeneration. Using both Ovid MEDLINE (n = 10) and Google Scholar (n = 10), we conducted a literature search relevant to treating the underlying causes of this disease with induced pluripotent stem cell (iPSC) therapy. In vitro studies of iPSC lines have demonstrated their ability to model neurodegeneration in DA neurons in addition to specific genetic risk factors, allowing for personalized pharmacological testing and treatment. In vivo studies have progressed over the last decade demonstrating the clinical safety and efficacy of iPSC transplantation in primate and human models. We present research that improves limitations of current methods, such as purification techniques, specific differentiation markers, cryopreservation of iPSCs, and CORIN sorting technology for large-scale production. Due to the evolution and improvement of these methods, we encourage the advancement and expansion of domestic PD-focused iPSC clinical trials.

TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson's Disease.

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson's Disease.

Parkinson’s disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [11C]UCB-J and [18F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [11C]UCB-J binding and [18F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuit’s cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [11C]UCB-J and [18F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

The Efek Neuroprotektif Kafein terhadap Fungsi Motorik pada Penyakit Parkinson

Abstract Background: Coffee is one of the most consumed drinks in the world and has become a routine part of everyday life. Coffee is known to be a stimulant because of its high caffeine content. Parkinson's disease is the second most common neurodegenerative disorder characterized by the clinical presentation of motor and non-motor disorders. Neuroinflammation plays a major role in the pathogenesis of Parkinson's disease which is regulated by reactive microglia and causes neurodegeneration of dopaminergic neurons. Consumption of caffeine can exert anti-inflammatory effects on nerves in a variety of pathological conditions. Method: The method used is a literature study from various national and international journals. This method is used with the aim of summarizing a current topic in order to increase an understanding. The literature study restates previously published material and reports new facts or analyzes from relevant literature studies and then compares the results in the article. Results: Caffeine can act as a neuroprotective against the development of Parkinson's disease by keeping the blood-brain barrier intact so that the function of the central nervous system remains stable. Caffeine can improve motor function in Parkinson's disease patients by modulating adenosine A2AR receptors at different doses. Caffeine as an adjuvant drug in the treatment of Parkinson's disease is given together with Trihexyphenidyl (THP) which is an anti-Parkinson's agent that has been used clinically to treat Parkinson's disease. Conclusion: Caffeine is a neuroprotective agent that is widely available and can be used in the treatment of Parkinson's disease with current therapies. However, the correct dosage and safety of caffeine are of particular concern, especially when given at high doses for a period of time and concurrently with other Parkinson's drugs.

The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo.

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.

A Flavonoid-Rich Extract of Mandarin Juice Counteracts 6-OHDA-Induced Oxidative Stress in SH-SY5Y Cells and Modulates Parkinson-Related Genes.

Parkinson’s disease (PD) is a degenerative disorder of the nervous system due to unceasing impairment of dopaminergic neurons situated in the substantia nigra. At present, anti-PD drugs acting on dopamine receptors are mainly symptomatic and have only very limited neuroprotective effects, whereas drugs slowing down neurodegeneration of dopaminergic neurons and deterioration of clinical symptoms are not yet available. Given that, the development of more valuable pharmacological strategies is highly demanded. Comprehensive research on innovative neuroprotective drugs has proven that anti-inflammatory and antioxidant molecules from food sources may prevent and/or counteract neurodegenerative diseases, such as PD. The present study was aimed at the evaluation the protective effect of mandarin juice extract (MJe) against 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma cell death. Treatment of differentiated SH-SY5Y cells with 6-OHDA brought cell death, and specifically, apoptosis, which was significantly inhibited by the preincubation with MJe through caspase 3 blockage and the modulation of p53, Bax, and Bcl-2 genes. In addition, it showed antioxidant properties in abiotic models as well as in vitro, where it reduced both reactive oxygen and nitrogen species induced by 6-OHDA, along with restored mitochondrial membrane potential, and prevented the oxidative DNA damage evoked by 6-OHDA. Furthermore, MJe restored the impaired balance of SNCA, LRRK2, PINK1, parkin, and DJ-1 gene levels, PD-related factors, caused by 6-OHDA oxidative stress. Overall, these results indicate that MJe exerts neuroprotective effects against 6-OHDA-induced cell death in SH-SY5Y cells by mechanisms involving both the specific interaction with intracellular pathways and its antioxidant capability. Our study suggests a novel possible strategy to prevent and/or ameliorate neurodegenerative diseases, such as PD.

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.

Venoms as an adjunctive therapy for Parkinson's disease: where are we now and where are we going?

Neurodegenerative diseases, including Parkinson’s disease (PD), are increasing in the aging population. Crucially, neurodegeneration of dopaminergic neurons in PD is associated with chronic inflammation and glial activation. Besides this, bradykinesia, resting tremor, rigidity, sensory alteration, and cognitive and psychiatric impairments are also present in PD. Currently, no pharmacologically effective treatment alters the progression of the disease. Discovery and development of new treatment strategies remains a focus for ongoing investigations. For example, one approach is cell therapy to prevent dopaminergic neuronal loss or to slow PD progression. The neuroprotective role of a diverse range of natural products, including venoms from bees, scorpions, snakes and lizards, are also being tested in preclinical PD models and in humans. The main findings from recent studies that have investigated venoms as therapeutic options for PD are summarized in this special report.

Molecular Mechanisms of Glutamate Toxicity in Parkinson's Disease.

Parkinson’s disease (PD) is a common neurodegenerative disease, the pathological features of which include the presence of Lewy bodies and the neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta. However, until recently, research on the pathogenesis and treatment of PD have progressed slowly. Glutamate and dopamine are both important central neurotransmitters in mammals. A lack of enzymatic decomposition of extracellular glutamate results in glutamate accumulating at synapses, which is mainly absorbed by excitatory amino acid transporters (EAATs). Glutamate exerts its physiological effects by binding to and activating ligand-gated ion channels [ionotropic glutamate receptors (iGluRs)] and a class of G-protein-coupled receptors [metabotropic glutamate receptors (mGluRs)]. Timely clearance of glutamate from the synaptic cleft is necessary because high levels of extracellular glutamate overactivate glutamate receptors, resulting in excitotoxic effects in the central nervous system. Additionally, increased concentrations of extracellular glutamate inhibit cystine uptake, leading to glutathione depletion and oxidative glutamate toxicity. Studies have shown that oxidative glutamate toxicity in neurons lacking functional N-methyl-D-aspartate (NMDA) receptors may represent a component of the cellular death pathway induced by excitotoxicity. The association between inflammation and excitotoxicity (i.e., immunoexcitotoxicity) has received increased attention in recent years. Glial activation induces neuroinflammation and can stimulate excessive release of glutamate, which can induce excitotoxicity and, additionally, further exacerbate neuroinflammation. Glutamate, as an important central neurotransmitter, is closely related to the occurrence and development of PD. In this review, we discuss recent progress on elucidating glutamate as a relevant neurotransmitter in PD. Additionally, we summarize the relationship and commonality among glutamate excitotoxicity, oxidative toxicity, and immunoexcitotoxicity in order to posit a holistic view and molecular mechanism of glutamate toxicity in PD.

Dopamine promotes the neurodegenerative potential of β‐synuclein

A contribution of α-Synuclein (α-Syn) to etiology of Parkinson´s disease (PD) and Dementia with Lewy bodies (DLB) is currently undisputed, while the impact of the closely related β-Synuclein (β-Syn) on these disorders remains enigmatic. β-Syn has long been considered to be an attenuator of the neurotoxic effects of α-Syn, but in a rodent model of PD β-Syn induced robust neurodegeneration in dopaminergic neurons of the substantia nigra. Given that dopaminergic nigral neurons are selectively vulnerable to neurodegeneration in PD, we now investigated if dopamine can promote the neurodegenerative potential of β-Syn. We show that in cultured rodent and human neurons a dopaminergic neurotransmitter phenotype substantially enhanced β-Syn-induced neurodegeneration, irrespective if dopamine is synthesized within neurons or up-taken from extracellular space. Nuclear magnetic resonance interaction and thioflavin-T incorporation studies demonstrated that dopamine and its oxidized metabolites 3,4-dihydroxyphenylacetaldehyde (DOPAL) and dopaminochrome (DCH) directly interact with β-Syn, thereby enabling structural and functional modifications. Interaction of DCH with β-Syn inhibits its aggregation, which might result in increased levels of neurotoxic oligomeric β-Syn. Since protection of outer mitochondrial membrane integrity prevented the additive neurodegenerative effect of dopamine and β-Syn, such oligomers might act at a mitochondrial level similar to what is suggested for α-Syn. In conclusion, our results suggest that β-Syn can play a significant pathophysiological role in etiology of PD through its interaction with dopamine metabolites and thus should be re-considered as a disease-relevant factor, at least for those symptoms of PD that depend on degeneration of nigral dopaminergic neurons.