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Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.

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With the recognition of the importance of the gut-brain axis in Parkinson's disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.

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Cellular replacement therapy and genetic transfer in injured brains provide new pathways for treating human neurological illnesses. Current progress in the field focuses on the production of neurons and glial cells from many types of stem cells, such as embryonic, induced pluripotent, mesenchymal, and neural stem cells. This has led to a significant increase in research on brain transplantation treatments. Extended neurodegeneration results in the progressive decline of certain neuronal subtypes or whole neuronal cells. An analysis of the progress made in induced pluripotent and mesenchymal stem cells reveals their significant promise in disease modeling, regeneration, and medication screening. The requirement for stem cells in neurodegenerative disease studies has been crucial in recent years. Stem cells provide the potential for replacing impaired neurons, comprehending disease needs modeling, and creating efficient treatments, but they have many challenges in culturing and acceptability to the host immune cells. The need to use their potential in discovering novel therapies for diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis leads to promising therapy. This review examines the function of stem cells in the pathogenesis and treatment of Huntington's disease, Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review further examines hurdles such as immunological reactions and delivery systems intending to overcome these problems. This article offers a detailed viewpoint on the use of stem cell-based nanotherapies as revolutionary treatments for various neurological illnesses.

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been widely linked to Parkinson's disease, where the G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events related to these mutations remain poorly understood. The advancement and availability of tools for neural engineering now enable modeling of selected pathological aspects of neurodegenerative disease in human neural networks in vitro. Our study revealed distinct pathology associated dynamics in engineered human cortical neural networks carrying the LRRK2 G2019S mutation compared to healthy isogenic control neural networks. The neurons carrying the LRRK2 G2019S mutation self-organized into networks with aberrant morphology and mitochondrial dynamics, affecting emerging structure-function relationships both at the micro-and mesoscale. Taken together, the findings of our study points toward an overall heightened metabolic demand in networks carrying the LRRK2 G2019S mutation, as well as a resilience to change in response to perturbation, compared to healthy isogenic controls.

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Transcription factor EB (TFEB) is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinson's disease (PD), and dementia with Lewy bodies (DLB). TFEB activation results in its translocation from the cytosol to the nucleus. Here, we investigated TFEB subcellular localization and its relation to intracellular alpha-synuclein (aSyn) accumulation in post-mortem human brain of individuals with either incidental Lewy body disease (iLBD), GBA-related PD/DLB (GBA-PD/DLB) or sporadic PD/DLB (sPD/DLB), compared to control subjects. We analyzed nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the TFEB subcellular localization patterns. We observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both in sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn accumulation in all groups. Importantly, we observed previously-unidentified TFEB-immunopositive perinuclear clusters in human dopaminergic neurons, which localized at the Golgi apparatus. These TFEB clusters were more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons, but also in neurons lacking detectable aSyn accumulation. In aSyn-negative cells, cytoplasmic TFEB clusters were more frequently observed in GBA-PD/DLB and iLBD patients, and correlated with reduced GBA enzymatic activity as well as increased Braak LB stage. Altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected TFEB-regulated genes, indicating a possible early dysfunction of lysosomal regulation. Overall, we observed cytoplasmic TFEB retention and accumulation at the Golgi in cells without apparent pSer129 aSyn accumulation in iLBD and PD/DLB patients. This suggests potential TFEB impairment at the early stages of cellular disease and underscores TFEB as a promising therapeutic target for synucleinopathies.

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OBJECTIVE: To evaluate the effects of transcranial direct current stimulation (tDCS) on Parkinson's disease (PD)-related pain. METHODS: This triple-blind randomized controlled trial included twenty-two patients (age range 38-85, 10 male) with PD-related pain. Eleven subjects received ten sessions of 20 minutes tDCS over the primary motor cortex contralateral to pain at 2 mA intensity. Eleven subjects received sham stimulation. Outcome measures included changes in the Kinǵs Parkinsons Pain Scale (KPPS), Brief Pain Inventory (BPI), widespread mechanical hyperalgesia (WMH), temporal summation of pain (TS), and conditioned pain modulation (CPM). RESULTS: Significant differences were found in KPPS between groups favoring the active-tDCS group compared to the sham-tDCS group at 15-days follow-up (p = 0.014) but not at 2 days post-intervention (p = 0.059). The active-group showed significant improvements over the sham-group after 15 days (p = 0.017). Significant changes were found in CPM between groups in favor of active-tDCS group at 2 days post-intervention (p = 0.002) and at 15 days (p = 0.017). No meaningful differences were observed in BPI or TS. CONCLUSIONS: tDCS of the primary motor cortex alleviates perceived PD-related pain, reduces pain sensitization, and enhances descending pain inhibition. SIGNIFICANCE: This is the first study to test and demonstrate the use of tDCS for improving PD-related pain.

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INTRODUCTION: One of the hallmarks of Parkinsons Disease (PD) is oxidative distress, leading to mitochondrial dysfunction and neurodegeneration. Insulin-like growth factor II (IGF-II) has been proven to have antioxidant and neuroprotective effects in some neurodegenerative diseases, including PD. Consequently, there isgrowing interest in understanding the different mechanisms involved in the neuroprotective effect of this hormone. OBJECTIVES: To clarify the mechanism of action of IGF-II involved in the protective effect of this hormone. METHODS: The present study was carried out on a cellular model PD based on the incubation of dopaminergic cells (SN4741) in a culture with the toxic 1-methyl-4-phenylpyridinium (MPP+), in the presence of IGF-II. This model undertakes proteomic analyses in order to understand which molecular cell pathways might be involved in the neuroprotective effect of IGF-II. The most important proteins found in the proteomic study were tested by Western blot, colorimetric enzymatic activity assay and immunocytochemistry. Along with the proteomic study, mitochondrial morphology and function were also studied by transmission electron microscopy and oxygen consumption rate. The cell cycle was also analysed using 7AAd/BrdU staining, and flow cytometry. RESULTS: The results obtained indicate that MPP+, MPP++IGF-II treatment and IGF-II, when compared to control, modified the expression of 197, 246 proteins and 207 respectively. Some of these proteins were found to be involved in mitochondrial structure and function, and cell cycle regulation. Including IGF-II in the incubation medium prevents the cell damage induced by MPP+, recovering mitochondrial function and cell cycle dysregulation, and thereby decreasing apoptosis. CONCLUSION: IGF-II improves mitochondrial dynamics by promoting the association of Mitofilin with mitochondria, regaining function and redox homeostasis. It also rebalances the cell cycle, reducing the amount of apoptosis and cell death by the regulation of transcription factors, such as Checkpoint kinase 1.

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Parkinson's Disease (PD) is characterized by classic motor symptoms related to movement, but PD patients can experience symptoms associated with impaired autonomic function, such as respiratory disturbances. Functional respiratory deficits are known to be associated with brainstem neurodegeneration in the mice model of PD induced by 6-hydroxydopamine (6-OHDA). Understanding the causes of neuronal death is essential for identifying specific targets to prevent degeneration. Many mechanisms can explain why neurons die in PD, and neuroinflammation is one of them. To test the influence of inflammation, mediated by microglia and astrocytes cells, in the respiratory disturbances associated with brainstem neurons death, we submitted wild-type (WT) and TNF receptor 1 (TNFR1) knockout male mice to the 6-OHDA model of PD. Also, male C57BL/6 animals were induced using the same PD model and treated with minocycline (45 mg/kg), a tetracycline antibiotic with anti-inflammatory properties. We show that degeneration of brainstem areas such as the retrotrapezoid nucleus (RTN) and the pre-Botzinger Complex (preBotC) were prevented in both protocols. Notably, respiratory disturbances were no longer observed in the animals where inflammation was suppressed. Thus, the data demonstrate that inflammation is responsible for the breathing impairment in the 6-OHDA-induced PD mouse model.

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The contribution of the immune system to the pathophysiology of neurodegenerative Parkinson's disease (PD) is increasingly being recognised, with alterations in the innate and adaptive arms of the immune system underlying central and peripheral inflammation in PD. As chief modulators of the immune response, cytokines have been intensely studied in the field of PD both in terms of trying to understand their contribution to disease pathogenesis, and if they may comprise much needed therapeutic targets for a disease with no current modifying therapy. This review summarises current knowledge on key cytokines implicated in PD (TNFα, IL-6, IL-1ß, IL-10, IL-4 and IL-1RA) that can modulate both pro-inflammatory and anti-inflammatory effects. Cytokine activity in PD is clearly a complicated process mediated by substantial cross-talk of signalling pathways and the need to balance pro- and anti-inflammatory effects. However, understanding cytokine activity may hold promise for unlocking new insight into PD and how it may be halted.

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This issue of JORH presents the first of a two-part series specifically exploring suicide. Research relating to moral injury is also included-a topic which has previously been discussed within earlier editions of JORH and an issue that is increasingly recognised as being associated with suicide. Other topic areas explored within this issue are Parkinson's Disease, Diabetes, and Haemodialysis. Finally, readers are once again reminded of the 9th European Congress on Religion, Spirituality and Health (ECRSH) to be held in May 2024, 16-18th at the Paracelsus Medical University in Salzburg, Austria. We would also like to announce a proposed inaugural International Moral Injury and Wellbeing Conference (IMIWC), 19-20 September 2024, Brisbane Exhibition and Convention Centre, Australia.

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Progressive supranuclear palsy (PSP) is a neurodegenerative condition that typically emerges in adulthood and does not exhibit any familial inheritance pattern. PSP is characterized by gradual stiffness in the central body, an inability to move the gaze upward voluntarily, postural instability, and a decline in cognitive function linked to frontal lobe dysfunction. Clinical assessment reveals a variety of findings, and cases of PSP frequently go unnoticed or are incorrectly diagnosed as other conditions. Notably, prominent neurotransmitter-related changes in PSP involve damage to the dopaminergic nigrostriatal pathway and cholinergic impairment in multiple regions. We hereby present a case of a 71-year-old female patient whose medical journey unfolds as a perplexing riddle. Despite the collective expertise of several physicians, she found herself bearing the weight of a misdiagnosis ascribed to Parkinson's Disease (PD) erroneously. She initially presented with recurring falls due to postural instability and bradykinesia, which progressed such that she became dependent on a walking aid. A comprehensive physical examination revealed indicators consistent with PSP.

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Background: Caffeine intake reduces risk of Parkinson's disease (PD), but the interaction with genes is unclear. The interaction of caffeine with genetic variants in those at high PD risk has healthcare importance. We investigate interactions of caffeine intake with risk variants found in Asians, and determine PD risk estimates in caffeine-drinkers carrying these variants. Methods: PD patients and controls without neurological disorders were included. Caffeine intake was assessed using a validated evaluation tool. Leucine rich repeat kinase 2 (LRRK2) risk variants were genotyped. Statistical analysis was conducted with logistic regression models. Gene-caffeine interactions were quantified using attributable proportion (AP) due to interaction (positive interaction defined as AP >0). Findings: 5100 subjects were screened and 4488 subjects (1790 PD, 2698 controls) with genetic data of at least one LRRK2 variant were included. Risk-variant-carriers who were non-caffeine-drinkers had increased PD odds compared to wildtype carriers who were caffeine-drinkers for G2385R [OR 8.6 (2.6-28.1) p < 0.001; AP = 0.71], R1628P [OR 4.6 (1.6-12.8) p = 0.004; AP = 0.50] and S1647T [OR 4.0 (2.0-8.1) p < 0.001; AP = 0.55] variants. Interpretation: Caffeine intake interacts with LRRK2 risk variants across three different groups of gene carriers. Asymptomatic risk-variant-carriers who are non-caffeine-drinkers have four to eight times greater PD risk compared to wildtype-caffeine-drinkers. Lifestyle modifications to mitigate PD risk in asymptomatic healthy risk variant carriers have potential roles in our Asian cohort. Funding: This study was supported by the National Medical Research Council (STaR and PD OF LCG 000207 grants) and Duke-NUS Medical School.

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with familial and sporadic forms of Parkinson's disease (PD). Sporadic PD and LRRK2 PD share main clinical and neuropathological features, namely hypokinesia, degeneration of nigro-striatal dopamine neurons and α-synuclein aggregates in the form of Lewy bodies. Animals harboring the most common LRRK2 mutations, i.e. p.G2019S and p.R1441C/G, have been generated to replicate the parkinsonian phenotype and investigate the underlying pathogenic mechanisms. Disappointingly, however, LRRK2 rodents did not consistently phenocopy hypokinesia and nigro-striatal degeneration, or showed Lewy body-like aggregates. Instead, LRRK2 rodents manifested non-motor signs and dysregulated transmission at dopaminergic and non-dopaminergic synapses that are reminiscent of behavioral and functional network changes observed in the prodromal phase of the disease. LRRK2 rodents also manifested greater susceptibility to different parkinsonian toxins or stressors when subjected to dual-hit or multiple-hit protocols, confirming LRRK2 mutations as genetic risk factors. In conclusion, LRRK2 rodents represent a unique tool to identify the molecular mechanisms through which LRRK2 modulates the course and clinical presentations of PD and to study the interplay between genetic, intrinsic and environmental protective/risk factors in PD pathogenesis.

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Adjunct therapy with the catechol-O-methyltransferase inhibitor entacapone is a first-line approach to treat wearing-off type motor fluctuations in levodopa-treated Parkinson's disease (PD) patients. Five randomized placebo-controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF-time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE-PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa-induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple-combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo® ) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate-release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end-of-dose wearing off.

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Enzymatic metabolism is the key determinant of the overall bioavailability, brain penetration, and efficacy of levodopa in the treatment of Parkinsons disease (PD). Enzyme inhibitors in the form of peripheral dopa-decarboxylase inhibitors and monoamine oxidase type-B inhibitors have been successfully employed to maximize the utility of levodopa in both early- and late-stage PD. However, another major pathway of the peripheral metabolism of levodopa through catechol-O-methyltransferase (COMT) remains unchecked by those measures. Consequently, this becomes a major factor in determining the extent of delivery to the brain. The introduction of tolcapone as a potent and effective peripheral and central COMT inhibitor was frustrated by the emergence of hepatic toxicity. Only with the subsequent introduction of entacapone as an effective inhibitor of peripheral COMT activity has it become possible to fully control the peripheral metabolism of levodopa and to optimize its delivery to the brain. At a single-dose level of 200 mg, the efficacy of entacapone in reducing OFF time and increasing ON time has led to its widespread use for the treatment of "wearing off". To maximize the efficacy of entacapone and to time-lock its pharmacokinetic profile to that of levodopa, a triple combination of levodopa, carbidopa, and entacapone in the form of Stalevo® that allowed for flexibility in levodopa dosing was introduced early in the 21st century. This pioneering development has been successfully used worldwide for the past 20 years. This review considers the role of all three classes of enzyme inhibitors in PD medicine.

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LRRK2 is a multi-domain protein with three catalytically inert N-terminal domains (NtDs) and four C-terminal domains, including a kinase and a GTPase domain. LRRK2 mutations are linked to Parkinson's Disease. Recent structures of LRRK2RCKW and a full-length inactive LRRK2 (fl-LRRK2INACT) monomer revealed that the kinase domain drives LRRK2 activation. The LRR domain and also an ordered LRR- COR linker, wrap around the C-lobe of the kinase domain and sterically block the substrate binding surface in fl-LRRK2INACT. Here we focus on the crosstalk between domains. Our biochemical studies of GTPase and kinase activities of fl-LRRK2 and LRRK2RCKW reveal how mutations influence this crosstalk differently depending on the domain borders investigated. Furthermore, we demonstrate that removing the NtDs leads to altered intramolecular regulation. To further investigate the crosstalk, we used Hydrogen-Deuterium exchange Mass Spectrometry (HDX-MS) to characterize the conformation of LRRK2RCKW   and Gaussian Accelerated Molecular Dynamics (GaMD) to create dynamic portraits of fl-LRRK2 and LRRK2RCKW. These models allowed us to investigate the dynamic changes in wild type and mutant LRRK2s. Our data show that the a3ROC helix, the Switch II motif in the ROC domain, and the LRR-ROC linker play crucial roles in mediating local and global conformational changes. We demonstrate how these regions are affected by other domains in fl-LRRK2 and LRRK2RCKW and show how unleashing of the NtDs as well as PD mutations lead to changes in conformation and dynamics of the ROC and kinase domains which ultimately impact kinase and GTPase activities. These allosteric sites are potential therapeutic targets.

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The accumulation of aggregated α-synuclein in susceptible neurons in the brain, together with robust activation of nearby myeloid cells, are pathological hallmarks of Parkinson's disease (PD). While microglia represent the dominant type of myeloid cell in the brain, recent genetic and whole-transcriptomic studies have implicated another type of myeloid cell, bone-marrow derived monocytes, in disease risk and progression. Monocytes in circulation harbor high concentrations of the PD-linked enzyme leucine-rich repeat kinase 2 (LRRK2) and respond to both intracellular and extracellular aggregated α-synuclein with a variety of strong pro-inflammatory responses. This review highlights recent findings from studies that functionally characterize monocytes in PD patients, monocytes that infiltrate into cerebrospinal fluid, and emerging analyses of whole myeloid cell populations in the PD-affected brain that include monocyte populations. Central controversies discussed include the relative contribution of monocytes acting in the periphery from those that might engraft in the brain to modify disease risk and progression. We conclude that further investigation into monocyte pathways and responses in PD, especially the discovery of additional markers, transcriptomic signatures, and functional classifications, that better distinguish monocyte lineages and responses in the brain from other types of myeloid cells may reveal points for therapeutic intervention, as well as a better understanding of ongoing inflammation associated with PD.

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BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological condition worldwide. Recent theories suggest that symptoms of PD may arise due to spread of Lewy-body pathology where the process begins in the gut and propagate transynaptically via the vagus nerve to the central nervous system. In PD, gait impairments are common motor manifestations that are progressive and can appear early in the disease course. As therapies to mitigate gait impairments are limited, novel interventions targeting these and their consequences, i.e., reducing the risk of falls, are urgently needed. Non-invasive vagus nerve stimulation (nVNS) is a neuromodulation technique targeting the vagus nerve. We recently showed in a small pilot trial that a single dose of nVNS improved (decreased) discrete gait variability characteristics in those receiving active stimulation relative to those receiving sham stimulation. Further multi-dose, multi-session studies are needed to assess the safety and tolerability of the stimulation and if improvement in gait is sustained over time. DESIGN: This will be an investigator-initiated, single-site, proof-of-concept, double-blind sham-controlled randomised pilot trial in 40 people with PD. Participants will be randomly assigned on a 1:1 ratio to receive either active or sham transcutaneous cervical VNS. All participants will undergo comprehensive cognitive, autonomic and gait assessments during three sessions over 24 weeks, in addition to remote monitoring of ambulatory activity and falls, and exploratory analyses of cholinergic peripheral plasma markers. The primary outcome measure is the safety and tolerability of multi-dose nVNS in PD. Secondary outcomes include improvements in gait, cognition and autonomic function that will be summarised using descriptive statistics. DISCUSSION: This study will report on the proportion of eligible and enrolled patients, rates of eligibility and reasons for ineligibility. Adverse events will be recorded informing on the safety and device tolerability in PD. This study will additionally provide us with information for sample size calculations for future studies and evidence whether improvement in gait control is enhanced when nVNS is delivered repeatedly and sustained over time. TRIAL REGISTRATION: This trial is prospectively registered at www.isrctn.com/ISRCTN19394828 . Registered August 23, 2021.

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The medicinal properties of cannabis and cannabinoid-derivative are entirely investigated and known. In addition, the identification of psychotropic plant cannabinoids has led to more studies regarding the cannabinoid system and its therapeutic features in the treatment and management of clinical symptoms of neuroinflammatory disorders, such as multiple sclerosis (MS), Parkinsons disease (PD), and Alzheimers disease (AD). In fact, cannabinoid agonists are able to control and regulate inflammatory responses. In contrast to the cannabinoid receptor type 1 (CB1) and its unwanted adverse effects, the cannabinoid receptor type 2 (CB2) and its ligands hold promise for new and effective therapeutic approaches. So far, some successes have been achieved in this field. This review will discuss an outline of the endocannabinoid system's involvement in neuroinflammatory disorders. Moreover, the pharmacological efficacy of different natural and synthetic preparations of phytocannabinoids acting on cannabinoid receptors, particularly in MS, PD, and AD, will be updated. Also, the reasons for targeting CB2 for neurodegeneration will be explained.

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