Pathophysiology Of Parkinson's Disease Research Articles

Gut-first Parkinson's disease is encoded by gut dysbiome.

In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood-brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain.

Microbiota Orchestra in Parkinson’s Disease: The Nasal and Oral Maestros

Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons, leading to a range of motor and non-motor symptoms. Background/Objectives: Over the past decade, studies have identified a potential link between the microbiome and PD pathophysiology. The literature suggests that specific bacterial communities from the gut, oral, and nasal microbiota may be involved in neuroinflammatory processes, which are hallmarks of PD. This review aims to comprehensively analyze the current research on the composition, diversity, and dysbiosis characteristics of the nasal and oral microbiota in PD. Methods: Through a comprehensive search across scientific databases, we identify twenty original studies investigating the nasal and oral microbiota in PD. Results: Most of these studies demonstrate the substantial roles of bacterial communities in neuroinflammatory pathways associated with PD progression. They also underscore the influences of microbiota-derived factors on key aspects of PD pathology, including alpha-synuclein aggregation and immune dysregulation. Conclusions: Finally, we discuss the potential diagnostic and therapeutic implications of modulating the nasal and oral microbiota in PD management. This analysis seeks to identify potential avenues for future research in order to clarify the complex relationships between these microorganisms and PD.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping.

Involvement of gastrointestinal inflammation in Parkinson's disease (PD) pathogenesis and movement have progressively emerged. Inflammation is involved in the etiology of both PD and inflammatory bowel disease (IBD). Transformations in leucine-rich recurrent kinase 2 (LRRK2) are among the best hereditary supporters of IBD and PD. Elevated levels of LRRK2 have been reported in stimulated colonic tissue from IBD patients and peripheral invulnerable cells from irregular PD patients; thus, it is thought that LRRK2 directs inflammatory cycles. Since its revelation, LRRK2 has been seriously linked in neurons, albeit various lines of proof affirmed that LRRK2 is profoundly communicated in invulnerable cells. Subsequently, LRRK2 might sit at a junction by which stomach inflammation and higher LRRK2 levels in IBD might be a biomarker of expanded risk for inconsistent PD or potentially may address a manageable helpful objective in incendiary sicknesses that increment the risk of PD. Here, we discuss how PD and IBD share covering aggregates, especially regarding LRRK2 and present inhibitors, which could be a helpful objective in ongoing treatments. English data were obtained from Google Scholar, PubMed, Scopus, and Cochrane library studies published between 1990-December 2022. Inhibitors of the LRRK2 pathway can be considered as the novel treatment approaches for IBD and PD treatment. Common mediators and pathways are involved in the pathophysiology of IBD and PD, which are majorly correlated with inflammatory situations. Such diseases could be used for further clinical investigations.

Decoding the Role of Nuclear Sirtuins in Parkinson's Pathogenesis.

Parkinson's disease (PD) is the second most prevailing degenerative disease that deals with dopaminergic neuronal loss and deficiency of dopamine in SNpc and striatum. Manifestations primarily include motor symptoms like tremor, rigidity, and akinesia/dyskinesia along with some nonmotor symptoms like GI and olfactory dysfunction. α-Synuclein pathogenesis is the major cause behind progression of PD; however there are many underlying molecular mechanisms behind the pathophysiology of PD. Sirtuins are small molecular deacetylases that have an imperative role in pathology of such neurodegenerative disorders like PD. Sirtuins are majorly classified according to their location; nuclear (SIRT1,7,6), mitochondrial sirtuins (SIRT3-5), and cytosolic (SIRT2). These actively take part in pathological development and possess independent actions. In this review, the role of nuclear sirtuins is individualistically explored for better understanding of PD pathology and development of advanced therapeutics targeting sirtuins.

A candidate loss-of-function variant in SGIP1 causes synaptic dysfunction and recessive parkinsonism

Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic "SH3GL2 Interacting Protein 1" (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network analysis of [18F]-fluorodeoxyglucose positron emission tomography scans shows patterns very similar to those of idiopathic Parkinson's disease. We show that the identified SGIP1 mutation causes a loss of protein function, and analyses in newly created Drosophila models reveal movement defects, synaptic transmission dysfunction, and neurodegeneration, including dopaminergic synapse loss. Histology and correlative light and electron microscopy reveal the absence of synaptic multivesicular bodies and the accumulation of degradative organelles. This research delineates a putative form of recessive parkinsonism, converging on defective synaptic proteostasis and opening avenues for diagnosis, genetic counseling, and treatment.

Investigating In Silico and In Vitro Therapeutic Potential of Diosmetin as the Anti-Parkinson Agent.

This study aimed to investigate how diosmetin interacts with seven target receptors associated with oxidative stress (OS) and validate its antioxidant properties for the potential management of Parkinson's disease (PD). In PD, the degeneration of dopaminergic cells is strongly influenced by OS. This stressor is intricately connected to various mechanisms involved in neurodegeneration, such as mitochondrial dysfunction, neuroinflammation, and excitotoxicity induced by nitric oxide. The aim of this research was to establish a molecular connection between diosmetin and OS-associated target receptors was the goal, and it investigated how this interaction can lessen PD. Seven molecular targets - Adenosine A2A (AA2A), Peroxisome Proliferator- Activated Receptor Gamma (PPARγ), Protein Kinase AKT1, Nucleolar Receptor NURR1, Liver - X Receptor Beta (LXRβ), Monoamine Oxidase - B (MAO-B) and Tropomyosin receptor kinase B (TrkB) were obtained from RCSB. Molecular docking software was employed to determine molecular interactions, while antioxidant activity was assessed through in-vitro assays against various free radicals. Diosmetin exhibited interactions with all seven target receptors at their binding sites. Notably, it showed superior interaction with AA2A and NURR1 compared to native ligands, with binding energies of -7.55, and -6.34 kcal/mol, respectively. Additionally, significant interactions were observed with PPARγ, AKT1, LXRβ, MAO-B, and TrkB with binding energies of -8.34, -5.42, -7.66, -8.82, -8.45 kcal/mol, respectively. Diosmetin also demonstrated antioxidant activity against various free radicals, particularly against hypochlorous acid (HOCl) and nitric oxide (NO) free radicals. Diosmetin possibly acts on several target receptors linked to the pathophysiology of PD, demonstrating promise as an OS inhibitor and scavenger.

Extract from Nasco pomace loaded in nutriosomes exerts anti-inflammatory effects in the MPTP mouse model of Parkinson's disease

Neuroinflammation has recently emerged as a key event in Parkinson's disease (PD) pathophysiology and as a potential target for disease-modifying therapies. Plant-derived extracts, rich in bioactive phytochemicals with antioxidant properties, have shown potential in this regard. Yet their clinical utility is hampered by poor systemic availability and rapid metabolism. Recently, our group demonstrated that intragastric delivery of Nasco pomace extract via nutriosomes (NN), a novel nanoliposome formulation, contrasts the degeneration of nigrostriatal dopaminergic neurons in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In the present study, we investigated the impact of intragastric NN treatment on the reactivity of glial cells in the substantia nigra pars compacta (SNc) and caudate-putamen (CPu) of MPTP-treated mice. To this scope, in mice exposed to MPTP (20 mg/kg/day, × 4 days), we conducted immunohistochemistry analyses of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA1) to assess the responsiveness of astrocytes and microglial cells, respectively. Additionally, we studied the co-localization of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF)-α with IBA1 to obtain insights into microglial phenotype. Immunohistochemical results showed that NN administration significantly mitigated astrogliosis and microgliosis in the CPu and SNc of mice receiving subacute MPTP treatment, with region-specific variations in anti-inflammatory efficacy. Remarkably, the CPu showed a heightened response to NN treatment, including a pronounced decrease in microglial IL-1β and TNF-α production. Altogether, these findings underscore the anti-inflammatory effects of NN treatment and provide a potential mechanism underlying the neuroprotective effects previously observed in a subacute MPTP mouse model of PD.

Role of Glutathione in Parkinson's Disease Pathophysiology and Therapeutic Potential of Polyphenols.

Oxidative stress is recognized to have a central role in the initiation and progression of Parkinson's disease (PD). Within the brain, neurons are particularly sensitive to oxidation due in part to their weak intrinsic antioxidant defense. Theoretically, neurons mostly depend on neighboring astrocytes to provide antioxidant protection by supplying cysteine-containing products for glutathione (GSH) synthesis. Astrocytes and neurons possess several amino acid transport systems for GSH and its precursors. Indeed, GSH is the most abundant intrinsic antioxidant in the central nervous system. The GSH depletion and/or alterations in its metabolism in the brain contribute to the pathogenesis of PD. Noteworthy, polyphenols possess potent antioxidant activity and can augment the GSH redox system. Numerous in vitro and in vivo studies have indicated that polyphenols exhibit potent neuroprotective effects in PD. Epidemiological studies have found an association between the consumption of dietary polyphenols and a lower PD risk. In this review, we summarize current knowledge on the biosynthesis and metabolism of GSH in the brain, with an emphasis on their contribution and therapeutic potential in PD. In particular, we focus on polyphenols that can increase brain GSH levels against PD. Furthermore, some current challenges and future perspectives for polyphenol-based therapies are also discussed.

Clinico-physiological correlates of Parkinson’s disease from multi-resolution basal ganglia recordings

Parkinson’s disease (PD) has been associated with pathological neural activity within the basal ganglia. Herein, we analyzed resting-state single-neuron and local field potential (LFP) activities from people with PD who underwent awake deep brain stimulation surgery of the subthalamic nucleus (STN; n = 125) or globus pallidus internus (GPi; n = 44), and correlated rate-based and oscillatory features with UPDRSIII off-medication subscores. Rate-based single-neuron features did not correlate with PD symptoms. STN single-neuron and LFP low-beta (12–21 Hz) power and burst dynamics showed modest correlations with bradykinesia and rigidity severity, while STN spiketrain theta (4–8 Hz) power correlated modestly with tremor severity. GPi low- and high-beta (21–30 Hz) power and burst dynamics correlated moderately with bradykinesia and axial symptom severity. These findings suggest that elevated single-neuron and LFP oscillations may be linked to symptoms, though modest correlations imply that the pathophysiology of PD may extend beyond resting-state beta oscillations.

Parkinson’s disease is associated with clonal hematopoiesis with TET2 mutation

Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson’s disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11–2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

Secondary parkinsonism associated with focal brain lesions.

Focal imaging abnormalities in patients with parkinsonism suggest secondary etiology and require a distinctive clinical approach to diagnosis and treatment. We review different entities presenting as secondary parkinsonism associated with structural brain lesions, with emphasis on the clinical course and neuroimaging findings. Secondary parkinsonism may be due to vascular causes, hydrocephalus, space-occupying lesions, metabolic causes (including acquired hepatocerebral degeneration, diabetic uremic encephalopathy, basal ganglia calcifications, osmotic demyelination syndrome), hypoxic-ischaemic brain injury, intoxications (including methanol, carbon monoxide, cyanide, carbon disulfide, manganese poisoning and illicit drugs), infections and immune causes. The onset can vary from acute to chronic. Both uni-and bilateral presentations are possible. Rigidity, bradykinesia and gait abnormalities are more common than rest tremor. Coexisting other movement disorders and additional associated neurological signs may point to the underlying diagnosis. Neuroimaging studies are an essential part in the diagnostic work-up of secondary parkinsonism and may point directly to the underlying etiology. We focus primarily on magnetic resonance imaging to illustrate how structural imaging combined with neurological assessment can lead to diagnosis. It is crucial that typical imaging abnormalities are recognized within the relevant clinical context. Many forms of secondary parkinsonism are reversible with elimination of the specific cause, while some may benefit from symptomatic treatment. This heterogeneous group of acquired disorders has also helped shape our knowledge of Parkinson's disease and basal ganglia pathophysiology, while more recent findings in the field garner support for the network perspective on brain function and neurological disorders.

Oxyphylla A exerts antiparkinsonian effects by ameliorating 6-OHDA-induced mitochondrial dysfunction and dyskinesia in vitro and in vivo

Parkinson's disease (PD) poses a formidable challenge in neurology, marked by progressive neuronal loss in the substantia nigra. Despite extensive investigations, understanding PD's pathophysiology remains elusive, with no effective therapeutic intervention identified to alter its course. Oxyphylla A (OPA), a natural compound extracted from Alpinia oxyphylla, exhibits promise in experimental models of various neurodegenerative disorders (ND), notably through novel mechanisms like α-synuclein degradation. The purpose of this investigation was to explore the neuroprotective potential of OPA on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PD models, with a focus on mitochondrial functions. Additionally, potential OPA targets for neuroprotection were explored. PC12 cells and C57BL/6 mice were lesioned with 6-OHDA as PD models. Impaired mitochondrial membrane potential (Δψm) was assessed using JC-1 staining. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were also detected to evaluate mitochondrial function and glucose metabolism in PC12 cells. Behavioral analysis and immunohistochemistry were performed to evaluate pathological lesions in the mouse brain. Moreover, bioinformatics tools predicted OPA targets. OPA restored cellular energy metabolism and mitochondrial biogenesis, preserving Δψm in 6-OHDA-induced neuronal damage. Pre-treatment mitigated loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and striatal dopaminergic fibers, restoring dopamine levels and ameliorating motor deficits in PD mice. Mechanistically, OPA may activate PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM signaling cascades. Bioinformatics analysis identified potential OPA targets, including CTNNB1, ESR1, MAPK1, MAPK14, and SRC. OPA, derived from Alpinia oxyphylla, exhibited promising neuroprotective activity against PD through addressing mitochondrial dysfunction, suggesting its potential as a multi-targeted therapeutic for PD.

Postmortem Fatty Acid Abnormalities in the Cerebellum of Patients with Essential Tremor.

Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem comparative analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n = 15), Parkinson's disease (PD) patients (n = 15) and Controls (n = 17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients compared with PD patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA). The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI + PS fractions. However, relative PI + PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.

Association between plasma Netrin-1 levels and motor and nonmotor symptoms in Parkinson's disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and diverse motor and nonmotor symptoms. Early diagnosis and intervention are crucial but challenging due to reliance on clinical presentation. Recent research suggests potential biomarkers for early detection, including plasma netrin-1 (NTN-1), a protein implicated in neuronal survival. This cross-sectional study recruited 105 PD patients and 65 healthy controls, assessing plasma NTN-1 levels and correlating them with clinical characteristics. Statistical analyses explored associations between NTN-1 levels and PD symptoms, considering demographic factors. PD patients exhibited significantly lower plasma NTN-1 levels compared to controls. NTN-1 demonstrated moderate potential as a PD biomarker. Positive correlations were found between NTN-1 levels and motor, depression, and cognitive symptoms. Multiple regression analysis revealed disease duration and NTN-1 levels as key factors influencing symptom severity. Gender also impacted symptom scores. Reduced plasma NTN-1 levels correlate with PD severity, suggesting its potential as a biomarker. However, further research is needed to elucidate the roles of NTN-1 in PD pathophysiology and validate its diagnostic and therapeutic implications. Understanding the involvement of NTN-1 may lead to personalized management strategies for PD.

MicroRNAs Modulating Neuroinflammation in Parkinson's disease.

Parkinson's disease (PD) is one of the most frequent age-associated neurodegenerative disorder. Presence of α-synuclein-containing aggregates in the substantia nigra pars compacta (SNpc) and loss of dopaminergic (DA) neurons are among the characteristic of PD. One of the hallmarks of PD pathophysiology is chronic neuroinflammation. Activation of glial cells and elevated levels of pro-inflammatory factors are confirmed as frequent features of the PD brain. Chronic secretion of pro-inflammatory cytokines by activated astrocytes and microglia exacerbates DA neuron degeneration in the SNpc. MicroRNAs (miRNAs) are among endogenous non-coding small RNA with the ability to perform post-transcriptional regulation in target genes. In that regard, the capability of miRNAs for modulating inflammatory signaling is the center of attention in many investigations. MiRNAs could enhance or limit inflammatory signaling, exacerbating or ameliorating the pathological consequences of extreme neuroinflammation. This review summarizes the importance of inflammation in the pathophysiology of PD. Besides, we discuss the role of miRNAs in promoting or protecting neural cell injury in the PD model by controlling the inflammatory pathway. Modifying the neuroinflammation by miRNAs could be considered a primary therapeutic strategy for PD.

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.

Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes.

Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.

The pathogenesis and treatment of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease that primarily affects middle-aged and older adults. Its incidence is second only to that of Alzheimer's disease. The primary source of clinical symptoms is the degradation and death of dopaminergic neurons in the substantia nigra-striatum. Patients mainly show motor symptoms such as static tremor, rigidity, bradykinesia and postural instability, and non-motor symptoms such as sensory disturbance, autonomic nervous dysfunction and mental cognitive impairment. There is no proven way to cure the disease or to slow its progression through neuroprotection, therefore treatment focuses mostly on treating symptoms. This study examines the shared pathophysiology of PD, which includes inflammation, abnormalities in protein handling, oxidative stress, and mitochondrial dysfunction. Next it discusses the available PD treatment options, which include standard medication therapy, promising surgical procedures, gene therapy, and new approaches to individualized PD care. The safety and usefulness of many treatments are still unknown, though. Hope that as life science and technology advance, the etiology of Parkinson's disease will become clearer and more dependable treatment options will be created to enhance sufferers' quality of life.

Serum Levels of Plasminogen Activator Inhibitor-1 in Patients with Parkinson's Disease.

To investigate serum plasminogen activator inhibitor-1 (PAI-1) levels of patients with Parkinson's disease (PD) and their relationship with clinical findings and treatment of disease. The study included 125 PD patients and 48 healthy controls. Patients have been taking effective dopaminergic treatment regularly. The clinical severity of parkinsonism was assessed using the Hoehn and Yahr (HY) staging scale and Unified PD Rating Scale (UPDRS). PAI-1 level analysis was performed by enzyme-linked immunosorbent assay. Patients with PD had significantly lower serum PAI-1 levels than healthy controls (p < 0.001). Correlations with clinical findings showed only marginally positive correlation between serum PAI-1 and HY score (r = 0.170, p = 0.05). In contrast, no significant correlation was demonstrated with the UPDRS score or other clinical parameters. This is the first comprehensive analysis of serum PAI-1 levels in patients with PD. The distribution of PAI-1 in PD appears to be complex. The study results implicate that the paradoxical effects of tissue plasminogen activator on the brain parenchyma can be important in the pathophysiology of PD. Future studies are needed to elucidate the role of fibrinolytic system components in PD.