Parkinson's Disease Therapy Research Articles

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.

The Role of Exercise in Maintaining Mitochondrial Proteostasis in Parkinson's Disease.

Parkinson's disease (PD) is the second most common rapidly progressive neurodegenerative disease and has serious health and socio-economic consequences. Mitochondrial dysfunction is closely related to the onset and progression of PD, and the use of mitochondria as a target for PD therapy has been gaining traction in terms of both recognition and application. The disruption of mitochondrial proteostasis in the brain tissue of PD patients leads to mitochondrial dysfunction, which manifests as mitochondrial unfolded protein response, mitophagy, and mitochondrial oxidative phosphorylation. Physical exercise is important for the maintenance of human health, and has the great advantage of being a non-pharmacological therapy that is non-toxic, low-cost, and universally applicable. In this review, we investigate the relationships between exercise, mitochondrial proteostasis, and PD and explore the role and mechanisms of mitochondrial proteostasis in delaying PD through exercise.

Assessing the Location, Relative Expression and Subclass of Dopamine Receptors in the Cerebellum of Hemi-Parkinsonian Rats

Parkinson’s Disease (PD) is a neurodegenerative disease with loss of dopaminergic neurons in the nigrostriatal pathway resulting in basal ganglia (BG) dysfunction. This is largely why much of the preclinical and clinical research has focused on pathophysiological changes in these brain areas in PD. The cerebellum is another motor area of the brain. Yet, if and how this brain area responds to PD therapy and contributes to maintaining motor function fidelity in the face of diminished BG function remains largely unanswered. Limited research suggests that dopaminergic signaling exists in the cerebellum with functional dopamine receptors, tyrosine hydroxylase (TH) and dopamine transporters (DATs); however, much of this information is largely derived from healthy animals and humans. Here, we identified the location and relative expression of dopamine 1 receptors (D1R) and dopamine 2 receptors (D2R) in the cerebellum of a hemi-parkinsonian male rat model of PD. D1R expression was higher in PD animals compared to sham animals in both hemispheres in the purkinje cell layer (PCL) and granule cell layer (GCL) of the cerebellar cortex. Interestingly, D2R expression was higher in PD animals than sham animals mostly in the posterior lobe of the PCL, but no discernible pattern of D2R expression was seen in the GCL between PD and sham animals. To our knowledge, we are the first to report these findings, which may lay the foundation for further interrogation of the role of the cerebellum in PD therapy and/or pathophysiology.

Neurodifferentiation and Neuroprotection Potential of Mesenchymal Stromal Cell-Derived Secretome Produced in Different Dynamic Systems.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of the dopamine (DA) neurons in the substantia nigra pars compacta, leading to a loss of DA in the basal ganglia. The presence of aggregates of alpha-synuclein (α-synuclein) is seen as the main contributor to the pathogenesis and progression of PD. Evidence suggests that the secretome of mesenchymal stromal cells (MSC) could be a potential cell-free therapy for PD. However, to accelerate the integration of this therapy in the clinical setting, there is still the need to develop a protocol for the large-scale production of secretome under good manufacturing practices (GMP) guidelines. Bioreactors have the capacity to produce large quantities of secretomes in a scalable manner, surpassing the limitations of planar static culture systems. However, few studies focused on the influence of the culture system used to expand MSC, on the secretome composition. In this work, we studied the capacity of the secretome produced by bone marrow-derived mesenchymal stromal cells (BMSC) expanded in a spinner flask (SP) and in a Vertical-Wheel™ bioreactor (VWBR) system, to induce neurodifferentiation of human neural progenitor cells (hNPCs) and to prevent dopaminergic neuron degeneration caused by the overexpression of α-synuclein in one Caenorhabditis elegans model of PD. Results showed that secretomes from both systems were able to induce neurodifferentiation, though the secretome produced in the SP system had a greater effect. Additionally, in the conditions of our study, only the secretome produced in SP had a neuroprotective potential. Lastly, the secretomes had different profiles regarding the presence and/or specific intensity of different molecules, namely, interleukin (IL)-6, IL-4, matrix metalloproteinase-2 (MMP2), and 3 (MMP3), tumor necrosis factor-beta (TNF-β), osteopontin, nerve growth factor beta (NGFβ), granulocyte colony-stimulating factor (GCSF), heparin-binding (HB) epithelial growth factor (EGF)-like growth factor (HB-EGF), and IL-13. Overall, our results suggest that the culture conditions might have influenced the secretory profiles of cultured cells and, consequently, the observed effects. Additional studies should further explore the effects that different culture systems have on the secretome potential of PD.

Neuroprotective Effect of Mangiferin against Parkinson's Disease through G-Protein-Coupled Receptor-Interacting Protein 1 (GIT1)-Mediated Antioxidant Defense.

Parkinson's disease (PD), known as a neurodegenerative disease, is characterized by movement disorders, with increasing age being the predominant risk factor for its development. Mangiferin, a bioactive compound isolated from mango, shows potent neuroprotection. In our work, we investigated the neuroprotection and mechanisms of mangiferin against PD. We established PD models by treating SH-SY5Y cells with rotenone and mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and investigated the therapeutic effects of mangiferin. Our results showed that mangiferin exhibited a cell-protective effect. Mangiferin also improved the motor behavior and attenuated the activation of microglia and astrocytes in MPTP mice. In addition, mangiferin decreased reactive oxygen species (ROS) levels and increased glutathione (GSH) and superoxide dismutase (SOD). Mangiferin also markedly activated GIT1, p-ERK, Nrf2, HO-1, and SOD expression and inhibited Keap1 expression in vitro and in vivo. To further investigate the role of GIT1, GIT1 siRNA was used. In the presence of GIT1 siRNA, the neuroprotection of mangiferin in PD was weakened. Our results indicate that mangiferin exhibited its therapeutic effect against PD by regulating GIT1 and its downstream Keap1/Nrf2 pathways. Our studies exhibited that mangiferin showed neuroprotection in PD, and its main target was GIT1. What is more, mangiferin could reduce the oxidative stress of PD by targeting GIT1 and its downstream Keap1/Nrf2 pathways. These indicated that mangiferin is a good candidate for PD therapy. However, the role of p-ERK in mangiferin-treated PD requires further investigation.

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson's disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.

Microglia Mediated Neuroinflammation in Parkinson's Disease.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder seen, especially in the elderly. Tremor, shaking, movement problems, and difficulty with balance and coordination are among the hallmarks, and dopaminergic neuronal loss in substantia nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein are the pathological characterizations. Neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. It is a complex network of interactions comprising immune and non-immune cells in addition to mediators of the immune response. Microglia, the resident macrophages in the CNS, take on the leading role in regulating neuroinflammation and maintaining homeostasis. Under normal physiological conditions, they exist as "homeostatic" but upon pathological stimuli, they switch to the "reactive state". Pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes are used to classify microglial activity with each phenotype having its own markers and released mediators. When M1 microglia are persistent, they will contribute to various inflammatory diseases, including neurodegenerative diseases, such as PD. In this review, we focus on the role of microglia mediated neuroinflammation in PD and also signaling pathways, receptors, and mediators involved in the process, presenting the studies that associate microglia-mediated inflammation with PD. A better understanding of this complex network and interactions is important in seeking new therapies for PD and possibly other neurodegenerative diseases.

Novel druggable mechanism of Parkinson's disease: Potential therapeutics and underlying pathogenesis based on ferroptosis.

Genetics, age, environmental factors, and oxidative stress have all been implicated in the development of Parkinson's disease (PD); however, a complete understanding of its pathology remains elusive. At present, there is no cure for PD, and currently available therapeutics are insufficient to meet patient needs. Ferroptosis, a distinctive iron-dependent cell death mode characterized by lipid peroxidation and oxidative stress, has pathophysiological features similar to those of PD, including iron accumulation, reactive oxygen species-induced oxidative damage, and mitochondrial dysfunction. Ferroptosis has been identified as a specific pathway of neuronal death and is closely related to the pathogenesis of PD. Despite the similarities in the biological targets involved in PD pathogenesis and ferroptosis, the relationship between novel targets in PD and ferroptosis has been neglected in the literature. In this review, the mechanism of ferroptosis is discussed, and the potential therapeutic targets implicated in both PD and ferroptosis are compared. Furthermore, the anti-PD effects of several ferroptosis inhibitors, as well as clinical studies thereof, and the identification of novel lead compounds for the treatment of PD and the inhibition of ferroptosis are reviewed. It is hoped that this review can promote research to further elucidate the relationship between ferroptosis and PD and provide new strategies for the development of novel ferroptosis-targeting PD therapy.

Learning critically drives parkinsonian motor deficits through imbalanced striatal pathway recruitment

Dopamine(DA) loss in Parkinson's disease (PD) causes debilitating motor deficits. However, dopamine is also widely linked to reward prediction and learning, and the contribution of dopamine-dependent learning to movements that are impaired in PD-which often do not lead to explicit rewards-is unclear. Here, we used two distinct motor tasks to dissociate dopamine's acute motoric effects vs. its long-lasting, learning-mediated effects. In dopamine-depleted mice, motor task performance gradually worsened with task exposure. Task experience was critical, as mice that remained in the home cage during the same period were relatively unimpaired when subsequently probed on the task. Repeated dopamine replacement treatments acutely rescued deficits and gradually induced long-term rescue that persisted despite treatment withdrawal. Surprisingly, both long-term rescue and parkinsonian performance decline were task specific, implicating dopamine-dependent learning. D1R activation potently induced acute rescue that gradually consolidated into long-term rescue. Conversely, reduced D2R activation potently induced parkinsonian decline. In dopamine-depleted mice, either D1R activation or D2R activation prevented parkinsonian decline, and both restored balanced activation of direct vs. indirect striatal pathways. These findings suggest that reinforcement and maintenance of movements-even movements not leading to explicit rewards-are fundamental functions of dopamine and provide potential mechanisms for the hitherto unexplained "long-duration response" by dopaminergic therapies in PD.

Potassium Channels in Parkinson's Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the midbrain. The loss of neurons results in a subsequent reduction of dopamine in the striatum, which underlies the core motor symptoms of PD. To date, there are no effective treatments to stop, slow, or reverse the pathologic progression of dopaminergic neurodegeneration. This unfortunate predicament is because of the current early stages in understanding the biologic targets and pathways involved in PD pathogenesis. Ion channels have become emerging targets for new therapeutic development for PD due to their essential roles in neuronal function and neuroinflammation. Potassium channels are the most prominent ion channel family and have been shown to be critically important in PD pathology because of their roles in modulating neuronal excitability, neurotransmitter release, synaptic transmission, and neuroinflammation. In this review, members of the subfamilies of voltage-gated K+ channels, inward rectifying K+ channels, and Ca2+-activated K+ channels are described. Evidence of the role of these channels in PD etiology is discussed together with the latest views on related pathologic mechanisms and their potential as biologic targets for developing neuroprotective drugs for PD. SIGNIFICANCE STATEMENT: Parkinson's disease (PD) is the second most common neurodegenerative disorder, featuring progressive degeneration of dopaminergic neurons in the midbrain. It is a multifactorial disease involving multiple risk factors and complex pathobiological mechanisms. Mounting evidence suggests that ion channels play vital roles in the pathogenesis and progression of PD by regulating neuronal excitability and immune cell function. Therefore, they have become "hot" biological targets for PD, as demonstrated by multiple clinical trials of drug candidates targeting ion channels for PD therapy.

Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice

Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy.

Neurotherapeutic Effects of Quercetin and Its Metabolite Compounds on Cognitive Impairment and Parkinson's Disease: An In Silico Study.

Little is known about the metabolomic profile of quercetin and its biological effects. This study aimed to determine the biological activities of quercetin and its metabolite products, as well as the molecular mechanisms of quercetin in cognitive impairment (CI) and Parkinson's disease (PD). Key methods used were MetaTox, PASS Online, ADMETlab 2.0, SwissADME, CTD MicroRNA MIENTURNE, AutoDock, and Cytoscape. A total of 28 quercetin metabolite compounds were identified by phase I reactions (hydroxylation and hydrogenation reactions) and phase II reactions (methylation, O-glucuronidation, and O-sulfation reactions). Quercetin and its metabolites were found to inhibit cytochrome P450 (CYP) 1A, CYP1A1, and CYP1A2. The studied compounds demonstrated significant gastrointestinal absorption and satisfied Lipinsky's criterion. Due to their high blood-brain barrier permeability, P-glycoprotein inhibition, anticancer, anti-inflammatory, and antioxidant capabilities, quercetin and its metabolite products have been proposed as promising molecular targets for the therapy of CI and PD. By regulating the expression of crucial signaling pathways [mitogen-activated protein kinase (MAPK) signaling pathway, and neuroinflammation and glutamatergic signaling], genes [brain derived neurotrophic factor (BDNF), human insulin gene (INS), and dopamine receptor D2 (DRD2), miRNAs (hsa-miR-16-5p, hsa-miR-26b-5p, hsa-miR-30a-5p, hsa-miR-125b-5p, hsa-miR-203a-3p, and hsa-miR-335-5p], and transcription factors [specificity protein 1 (SP1), v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), and nuclear factor Kappa B subunit 1 (NFKB1)], quercetin exhibited its neurotherapeutic effects in CI and PD. In addition to inhibiting β-N-acetylhexosaminidase, quercetin also showed robust interactions and binding affinities with heme oxygenase 1 (HMOX1), superoxide dismutase 2 (SOD2), tumor necrosis factor (TNF), nitric oxide synthase 2 (NOS2), brain-derived neurotrophic factor (BDNF), INS, DRD2, and γ-aminobutyric acid type A (GABAa). This study identified 28 quercetin metabolite products. The metabolites have similar characteristics to quercetin such as physicochemical properties, absorption, distribution, metabolism, and excretion (ADME), and biological activities. More research, especially clinical trials, is needed to find out how quercetin and its metabolites protect against CI and PD.

Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition.

Macroautophagy is a catabolic process that coordinates with lysosomes to degrade aggregation-prone proteins and damaged organelles. Loss of macroautophagy preferentially affects neuron viability and is associated with age-related neurodegeneration. We previously found that α-synuclein (α-syn) inhibits lysosomal function by blocking ykt6, a farnesyl-regulated soluble NSF attachment protein receptor (SNARE) protein that is essential for hydrolase trafficking in midbrain neurons. Using Parkinson's disease (PD) patient iPSC-derived midbrain cultures, we find that chronic, endogenous accumulation of α-syn directly inhibits autophagosome-lysosome fusion by impairing ykt6-SNAP-29 complexes. In wild-type (WT) cultures, ykt6 depletion caused a near-complete block of autophagic flux, highlighting its critical role for autophagy in human iPSC-derived neurons. In PD, macroautophagy impairment was associated with increased farnesyltransferase (FTase) activity, and FTase inhibitors restored macroautophagic flux through promoting active forms of ykt6 in human cultures, and male and female mice. Our findings indicate that ykt6 mediates cellular clearance by coordinating autophagic-lysosomal fusion and hydrolase trafficking, and that macroautophagy impairment in PD can be rescued by FTase inhibitors.SIGNIFICANCE STATEMENT The pathogenic mechanisms that lead to the death of neurons in Parkinson's disease (PD) and Dementia with Lewy bodies (LBD) are currently unknown. Furthermore, disease modifying treatments for these diseases do not exist. Our study indicates that a cellular clearance pathway termed autophagy is impaired in patient-derived culture models of PD and in vivo We identified a novel druggable target, a soluble NSF attachment protein receptor (SNARE) protein called ykt6, that rescues autophagy in vitro and in vivo upon blocking its farnesylation. Our work suggests that farnesyltransferase (FTase) inhibitors may be useful therapies for PD and DLB through enhancing autophagic-lysosomal clearance of aggregated proteins.

The deficiency of Maged1 attenuates Parkinson's disease progression in mice

Melanoma-associated antigen D1 (Maged1) has critical functions in the central nervous system in both developmental and adult stages. Loss of Maged1 in mice has been linked to depression, cognitive disorder, and drug addiction. However, the role of Maged1 in Parkinson’s disease (PD) remains unclear. In this study, we observed that Maged1 was expressed in the dopaminergic (DA) neurons of the substantia nigra in mice and humans, which could be upregulated by the in vivo or in vitro treatment with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-Methyl-4-phenylpyridinium iodide (MPP+). Genetic ablation of Maged1 in mice attenuated motor deficits, the loss of DA neurons, and disease progression induced by MPTP. Moreover, Maged1 deficiency protected DA neurons against MPP+-induced toxicity in primary cultured cells. Mechanistically, loss of Maged1 upregulated the Akt signaling pathway and downregulated the mTOR signaling pathway in SH-SY5Y cells, which may in turn attenuate the cell apoptosis and impairment of autophagy. Consistent with it, the degeneration of midbrain and striatum among elderly Maged1 knockout mice was relatively mild compared to those in wild-type mice under physiological conditions. Taken together, this study suggested that Maged1 deficiency inhibited apoptosis and enhanced autophagy, which may provide a new potential target for the therapy of PD.

Modulating SQSTM1/p62-dependent selective autophagy of neurons by activating Nrf2 with multifunctional nanoparticles to eliminate α-synuclein aggregates and boost therapy of Parkinson’s disease

The misfolding and aggregation of α-synuclein is one of the key pathogeneses in Parkinson's disease (PD). Development of innovative and effective approaches to eliminate α-synuclein aggregates is crucial for PD treatment. Herein, we report that quercetin-modified ultrasmall Cu2-xSe antioxidative nanoparticles (abbreviated as CSPQ) can promote neurons to efficiently scavenge α-synuclein aggregates and boost PD therapy by activating their nuclear factor-erythroid 2-related factor 2 (Nrf2) to enhance the SQSTM1/p62-dependent selective autophagy. We reveal that CSPQ nanoparticles can promote the degradation of Kelch-like ECH-associated protein 1 (Keap1) and thus activate Nrf2/p62 pathway of neurons by stimulating their nuclear translocation of transcription factor EB (TFEB). Moreover, these nanoparticles can successfully reduce α-synuclein associated pathology to alleviate neuronal damage in vivo and improve motor disorder and exploration ability of α-synuclein preformed fibrils (PFFs)-induced PD mice. Our work demonstrates the importance and novelty of modulating the selective autophagy of neurons by nanoparticles in clearance of α-synuclein aggregates for PD therapy, and highlights the great potential of CSPQ nanoparticles in PD therapy.

A Review of Genetic and Gene Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a syndrome with deterioration of neurons, with its onset starting in the '20s, known as the young beginning of Parkinson's to the late inception of the ailment in the 60s. The majority of the environmental risk associated with PD is age. The pathophysiology of PD is related to the accretion of synuclein alpha (SNCA) protein leading to toxicity. This toxicity further leads to a depletion in dopamine levels, creating both motor and non-motor symptoms. PD is the combination of genetic and environmental risk factors. Linkage and association studies provided data on autosomal dominant and recessive genes linked to PD. Current treatment regimes involve using levodopa, catechol-O-methyl transferase inhibitors, anticholinergics, and monoamine oxidase B (MAO-B) inhibitors. Genetic treatment is done by identifying possible targets. Gene therapy includes silencing, replacing, or correcting the flawed gene with a good gene. This therapy has the advantage of eliminating significant PD symptoms with fewer to no adverse effects than conventional treatment. These targets are organized into disease-modifying or non-disease modifying. The distinction between these two is that disease-modifying treatment stops the degeneration of neurons, while non-disease modifying treatment involves dopaminergic enzyme expression. In non-modifying targets, aromatic L-amino acid decarboxylase (AADC) therapy is used but not as a standalone, so the presentation of AADC, tyrosine hydroxylase (TH), and GTP cyclohydrolase 1 (GCH) is done together as a tricistronic system. With these developments, a drug named prosavin is under clinical phase 1 trial. Disease-modifying targets involve glial cell-derived neurotrophic factor (GDNF). Direct GDNF delivery reduces PD symptoms. This GDNF infusion technique works with a tetracycline-controlled transactivator. Gene therapy introduction into the treatment of PD would be beneficial as there would be lesser adverse effects seen as linked with conventional treatment involving levodopa, MAO-B inhibitors, and anticholinergics, among a few. This article discusses the genetic basis and genetic model of therapy for PD.

ASC specks exacerbate α‑synuclein pathology via amplifying NLRP3 inflammasome activities

BackgroundInflammasome activation has a pathogenic role in Parkinson’s disease (PD). Up-regulated expressions of inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and assembly of ASC specks have been observed in postmortems of human PD brains and experimental PD models. Extracellular ASC specks behave like danger signals and sustain prolonged inflammasome activation. However, the contribution of ASC specks in propagation of inflammasome activation and pathological progression in PD has not been fully established.MethodsHerein, we used human A53T mutant α-synuclein preformed fibrils (PFFs)-stimulated microglia in vitro and unilateral striatal stereotaxic injection of PFFs-induced mice model of PD in vivo, to investigate the significance of ASC specks in PD pathological progression. Rotarod and open-field tests were performed to measure motor behaviors of indicated mice. Changes in the molecular expression were evaluated by immunofluorescence and immunoblotting (IB). Intracellular knockdown of the ASC in BV2 cells was performed using si-RNA. Microglial and neuronal cells were co-cultured in a trans-well system to determine the effects of ASC knockdown on cytoprotection.ResultsWe observed a direct relationship between levels of ASC protein and misfolded α‑synuclein aggregates in PD mice brains. ASC specks amplified NLRP3 inflammasome activation driven by α-synuclein PFFs stimulation, which aggravated reactive microgliosis and accelerated α‑synuclein pathology, dopaminergic neurodegeneration and motor deficits. Endogenous ASC knockdown suppressed microglial inflammasome activation and neuronal α‑synuclein aggregation.ConclusionsIn conclusion, our study elucidated that ASC specks contribute to the propagation of inflammasome activation-associated α‑synuclein pathology in PD, which forms the basis for targeting ASC as a potential therapy for PD.

Tele-Reha-Nachsorge

Telerehabilitation applications are increasingly used in neurorehabilitation, especially since the SARS-CoV-2 pandemic. Their acceptance by care providers, patients and payers has increased. In the field of multiple sclerosis (MS), stroke and Parkinson's disease therapy, positive effects of telerehabilitation on various disease parameters have been demonstrated in smaller studies in recent years. The "non-inferiority" to outpatient rehabilitation measures has been shown convincingly in some rehabilitation patient collectives. In Germany, the Federation of German Pension Insurance Institutions (DRV Bund) has created an opportunity for the dissemination of telerehabilitative procedures by establishing tele-rehab aftercare. Keywords: telerehabilitation, tele-rehab aftercare, MS, stroke, Parkinson's disease

Stimulus-responsive curcumin-based polydopamine nanoparticles for targeting Parkinson’s disease by modulating α-synuclein aggregation and reactive oxygen species

Parkinson’s disease (PD) is the second most common neurodegenerative disease, posing a significant threat to an individual’s health, particularly among the elderly. An incomplete understanding of the pathogenesis underlying PD renders the single therapeutic model ineffective. Oxidative stress and abnormal alpha-synuclein (α-Syn) aggregation are two crucial factors accounting for dopaminergic neuron loss. Therefore, combined PD therapy that inhibits and reduces α-Syn aggregation and regulates the balance of reactive oxygen species (ROS) holds promise. In this study a novel nanodrug, polydopamine-based curcumin-loaded nanoparticles (PC NPs), based on polydopamine (PDA)-assembled curcumin (Cur) nanoparticles was designed, which was then modified with a peptide obtained from rabies virus glycoprotein (RVG) 29 (obtained RPC NPs) to target the brain. Cur and PDA of ROS-responsive nanoparticles (RPC NPs) significantly scavenged a broad spectrum of ROS. Cur inhibited and removed α-Syn aggregation, thus protecting PC12 cells from rotenone-induced cell death. RPC NPs were also shown to prolong the lifespan of Caenorhabditis elegans and restored dopamine-dependent behaviors, including area-restricted searching, ethanol avoidance, and the basal slowing response, by using 6-hydroxydopamine (6-OHDA)-pretreated C. elegans wild-type Bristol (N2) and the nematode transgenic hus111 strain as models. In vivo animal studies showed that RPC NPs significantly lowered dopaminergic neuron damage and improved the neurobehavioral abnormalities in PD mice, while having no noticeable systemic side effects. RPC NPs also decreased α-Syn accumulation and reduced oxidative stress in the striatum and substantia nigra. This multifunctional synergetic strategy may provide a new candidate for highly efficient combination therapy in patients with PD.

Effects of Qigong Exercises on Patients with Parkinson’s Disease: A Follow-up Study

Qigong, a traditional Chinese exercise routine, has been used as a treatment for Parkinson’s disease (PD) in many studies, and the results have confirmed its effectiveness in reducing the symptoms of PD. However, no study has yet investigated the long-term effects and benefits of Qigong practices in improving the symptoms of PD. The purpose of this follow-up evaluation was to investigate the long-term effects of Qigong practices in improving the symptoms of PD. In this randomized controlled trial (RCT), patients in the moderate stage of PD (N = 15), who had been practicing Qigong exercises, agreed to participate in this follow-up measurement after the intervention. Two important indicators, the Timed Up and Go test (TUG) and the One-legged Blind Balance test, were used to measure the patients’ functional coordination and progressive balance capabilities. Results one year following the intervention were compared with data from the same patients at the 5<sup>th</sup> and 10<sup>th</sup> weeks in the previous RCT experimental group using repeated measures ANOVA. The results showed that the patients in this study demonstrated a significant improvement in the TUG test (P < 0.01) and balance ability test (P < 0.05). Qigong exercises can significantly improve the patients’ functional coordination and balance capabilities with moderate PD. Therefore, the Qigong exercise routine can be used as an effective long-term rehabilitation therapy for PD.