Pathophysiology Of Parkinson's Disease Research Articles

Revolutionizing Parkinson's treatment: Harnessing the potential of intranasal nanoemulsions for targeted therapy.

Parkinson's disease (PD) is the most prominent and highly prevalent chronic neuro-degenerative disease generally recognized by classical motor symptoms which are linked with genetic mutation, Lewy bodies, and subsequently selective loss of nigrostriatal dopaminergic neurons. The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier protect the central nervous system against toxins and are the most significant barriers to effectivebrain drug delivery in managing Parkinsonism. In recent years, intranasal delivery has attracted remarkable attention for brain targeting as the drug can be administered to the brain directly from the nose employing the trigeminal and olfactory pathways. For brain targeting through nasal delivery, several advanced and promising formulation techniques have been investigated globally. Nanoemulsions are regarded as an innovative carrier approach for PD, where these provide targeted administration and enhanced bioavailability of neurotherapeutics. This manuscript provides deeper insight into the pathophysiology of PD, various drug delivery strategies to overcome BBB, and the potential role of nanoemulsions via the intranasal route. Various research findings on the intranasal administration of nanoemulsions and their pivotal applications in the treatment of PD have also been embarked. The potential role of phytoconstituents and surface-modified nanoemulsions for the effective treatment of PD has also been reflected along with current challenges and future perspectives in this avenue.

Sex hormones shape EEG-based functional connectivity in early-stage Parkinson's disease patients.

Parkinson's disease (PD) epidemiology and clinical features are sexually dimorphic. However, there are no data based on EEG functional connectivity (FC). Likewise, the contribution of sex hormones on brain FC has never been evaluated. Here, we aimed to investigate the association between biological sex and sex hormones on cortical FC changes in PD using high-density EEG. This study involved 69 early-stage PD patients (F/M 27/42) and 69 age-matched healthy controls (HC) (F/M 30/39). Sex hormone levels (total-testosterone (TT), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)) were assessed in PD patients. Data were recorded with a 64-channel EEG system. Source reconstruction method was used to identify brain activity. Cortico-cortical FC was analysed based on the weighted phase-lag index (wPLI) in θ-α-β-low γ bands. Network-based statistic (NBS) was used to compare FC between genders in HC and PD and to study the relationship between FC and sex hormones in PD. PD exhibited a hypoconnected network at θ and α bands and a hyperconnected network at β band compared to HC. Male HC showed a hyperconnected network at α-band compared to female HC. Conversely, males with PD showed a hypoconnected network at α-band compared to females with PD. In females and males with PD, E2 positively correlated with α-FC, while gonadotropins positively correlated with β-FC. TT positively correlated with the θ-FC only in males. Sex hormones shape EEG-FC in both males and females with PD, supporting their major influence on PD pathophysiology.

Analysis of key lncRNA related to Parkinson's disease based on gene co-expression weight networks.

To identify a key Long chain non-coding RNAs (lncRNAs) related to PD and provide a new perspective on the role of LncRNAs in Parkinson's disease (PD) pathophysiology. Our study involved analyzing gene chips from the substantia nigra and white blood cells, both normal and PD-inclusive, in the Gene Expression Omnibus (GEO) database, utilizing a weighted gene co-expression network analysis (WGCNA). The technique of WGCNA facilitated the examination of differentially expressed genes (DEGs) in the substantia nigra and the white blood cells of individuals with PD. When merged with clinical data, gene modules containing crucial clinical details were chosen for network integration in GO and KEGG enrichment analysis. A pair of LncRNA modules were identified. The crucial component in GSE7621 was the turquoise module. The DEGs were acquired using GSE133347. GO functions focused on phosphatidylinositol phosphate binding, inflammatory responses, and the regulation of nerves and synapses. KEGG analyses were largely enriched within the P13K-Akt, FaxO, mTOR, Oxytocin, and cGMP-PKG signaling pathways. A Venn diagram revealed that the two key LncRNA were CH17-189H20.1 and RP11-168O16.1. Using the WGCNA method, we obtained PD-related modules, identified biologically significant gene modules, obtained core LncRNAs, and found potential target genes for enrichment analysis. The objective of our research was to advance more detailed and efficient treatment methods for lncRNAs associated with PD.

ASSOCIATION OF MELANOMA AND INCIDENCE OF PARKINSON’S DISEASE: A COHORT STUDY IN US VETERANS

Abstract Melanoma is associated with subsequent Parkinson’s disease (PD) and identifying the clinicopathologic properties of melanoma driving this association could give insight into PD pathophysiology. We undertook a retrospective cohort study of US military Veterans (n=13,737,081) to determine if malignant and premalignant phenotypes were associated with PD by using propensity score matching 4-to-1 and adjustment for competing risk of death and key confounders. Broad cancer categories were obtained from the Oncology VA registry. Data about melanoma were obtained from clinical and pathology reports using manually validated natural language processing. Risk difference and 95% confidence intervals (CI) were estimated by presence or absence of cancer. For broad cancer categories, we found decreased PD incidence associated with multiple malignancies with some novel associations (e.g. HR = 0.4 [0.2,0.5] for myeloma). In terms of melanoma, BRAF and NRAS mutational status was not associated with incident PD. Atypical/dysplastic nevi was associated with increased PD incidence (HR = 1.4 [1.2,1.7]). Melanoma subtypes in the Oncology registry were associated with PD and included superficial spreading type (HR = 1.8 [1.0, 3.3]) and lentigo maligna (HR = 1.6 [1.2, 2.1]). In people with VA pathology reports, this effect was replicated with greater effect size for superficial spreading type (HR = 10.4 [6.5,16.9]) and lentigo maligna (HR = 6.4 [3.4,11.8]) although adjustment for ascertainment bias is needed. These data show PD is associated with melanoma subtypes and precursor lesions and suggest screening for PD could be appropriate in those with melanocytic lesions once early diagnostic tests are developed.

Behavioral analysis of motor and non-motor impairment in rodent models of Parkinson's disease

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the degeneration of dopamine neurons in the substantia nigra pars compacta, leading to motor and non-motor symptoms. While motor symptoms such as rigidity, tremor, bradykinesia/akinesia, and postural instability are well-recognized, non-motor symptoms including cognitive decline, depression, and anxiety also significantly impact patients' quality of life. Preclinical research utilizing animal models has been instrumental in understanding PD pathophysiology and exploring therapeutic interventions. Various approaches, including genetic manipulations and toxin-induced insults, aim to recapitulate both motor and non-motor aspects of PD in animal models. However, no single model fully replicates the complex spectrum of PD symptoms. Behavioral assessments play a crucial role in evaluating motor impairments in PD animal models, focusing on the manifestation of Parkinsonian motor phenotype. These assessments encompass locomotor activities, motor behavior abnormalities, and induced rotational behavior. Similarly, non-motor features are assessed through tests evaluating behavioral alterations such as depression, anxiety, and cognitive impairment. Although numerous animal models of PD have been developed, including non-human primates and both mammalian and non-mammalian species, this review focuses on motor and non-motor testing methodologies in rodent models, which are the most commonly used. Emphasizing genetic and toxin-induced PD models in mice and rats, we highlight key testing strategies and the significance of each method in addressing specific research questions and interpreting experimental data. By providing a comprehensive overview of these testing approaches, this review aims to advance understanding and foster progress in PD research.

Immune Cell Distributions in the Blood of Healthy Individuals at High Genetic Risk of Parkinson's Disease.

The immune system likely plays a key role in Parkinson's disease (PD) pathophysiology. Thus, we investigated whether immune cell compositions are already altered in healthy individuals at high genetic risk for PD. We quantified 92 immune cell subtypes in the blood of 442 individuals using multicolor flow cytometry. Polygenic risk scores (PGS) for PD were calculated based on genome-wide significant SNPs (n = 87) from a large genome-wide association study (n = 1,530,403). Linear regression analyses did not reveal significant associations between PGS and any immune cell subtype (FDR = 0.05). Nominally significant associations were observed for NKG2C+ B cells (p = 0.026) in the overall sample. Older participants at increased genetic PD risk also showed a higher proportion of myeloid dendritic cells (p = 0.019) and CD27+CD4+ memory T cells (p = 0.043). Several immune cells were nominally statistically associated in women only. These findings suggest that major alterations of immune cells only occur later in the progression of PD.

Potential Regulation of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript1 by Estrogen in Parkinson’s Disease

Parkinson’s disease (PD) is the second-leading cause of death among neurodegenerative disease after Alzheimer’s disease (AD), affecting around 2% of the population. It is expected that the incidence of PD will exceed 12 million by 2040. Meanwhile, there is a recognized difference in the phenotypical expression of the disease and response to treatment between men and women. Men have twice the incidence of PD compared to women, who have a late onset and worse prognosis that is usually associated with menopause. In addition, the incidence of PD in women is associated with the cumulative estrogen levels in their bodies. These differences are suggested to be due to the protective effect of estrogen on the brain, which cannot be given in clinical practice to improve the symptoms of the disease because of its peripheral side effects, causing cancer in both males and females in addition to the feminizing effect it has on males. As PD pathophysiology involves alteration in the expression levels of multiple LncRNAs, including metastatic-associated lung adenocarcinoma transcript 1 (MALAT1), and as estrogen has been illustrated to control the expression of MALAT1 in multiple conditions, it is worth investigating the estrogen–MALAT1 interaction in Parkinson’s disease to mimic its protective effect on the brain while avoiding its peripheral side effects. The following literature review suggests the potential regulation of MALAT1 by estrogen in PD, which would enhance our understanding of the pathophysiology of the disease, improving the development of more tailored and effective treatments.

Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease.

The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented in Parkinson's disease (PD). The LC-NE neurodegeneration is believed to underlie various nonmotor symptoms in people with PD, including neuropsychiatric deficits, sleep disruptions, and cognitive impairments. Of particular interest, LC-NE neurons send intensive axonal projections to the motor regions of the cerebral cortex. However, how NE depletion in the motor cortex contributes to PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes in the cerebral cortex as LC-NE degenerates, which might involve its interaction with dopaminergic signaling during the chronic course of the disease. In the present article, we briefly discuss clinical and preclinical studies that support the critical roles of LC-NE neurodegeneration and motor cortical dysfunction in both motor and nonmotor deficits in Parkinsonian states. We focus our discussion on the potential impact of LC-NE neurodegeneration on motor cortical function and the subsequent symptom manifestation. Last, we propose future research directions that can advance our understanding of cortical pathophysiology in PD by integrating noradrenergic degeneration.

Mitochondrial dysfunction in Parkinson's disease.

The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.

The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons

BackgroundVariants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specific CTSB variants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previous in vitro studies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified.MethodsHere, we conducted genetic analyses of the association between common and rare CTSB variants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines, induced pluripotent stem cell-derived dopaminergic neurons and midbrain organoids and assessed lysosomal activity and the handling of aggregated synuclein fibrils.ResultsWe find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein.ConclusionsThese results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Functional anatomy of the subthalamic nucleus and the pathophysiology of cardinal features of Parkinson's disease unraveled by focused ultrasound ablation.

The subthalamic nucleus (STN) modulates basal ganglia output and plays a fundamental role in the pathophysiology of Parkinson's disease (PD). Blockade/ablation of the STN improves motor signs in PD. We assessed the topography of focused ultrasound subthalamotomy (n = 39) by voxel-based lesion-symptom mapping to identify statistically validated brain voxels with the optimal effect against each cardinal feature and their respective cortical connectivity patterns by diffusion-weighted tractography. Bradykinesia and rigidity amelioration were associated with ablation of the rostral motor STN subregion connected to the supplementary motor and premotor cortices, whereas antitremor effect was explained by lesioning the posterolateral STN projection to the primary motor cortex. These findings were corroborated prospectively in another PD cohort (n = 12). This work concurs with recent deep brain stimulation findings that suggest different corticosubthalamic circuits underlying each PD cardinal feature. Our results provide sound evidence in humans of segregated anatomy of subthalamic-cortical connections and their distinct role in PD pathophysiology and normal motor control.

Galantamine-Memantine Combination in the Treatment of Parkinson's Disease Dementia.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson's disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain. Due to its limited efficacy and side effect profile, rivastigmine is often not prescribed, leaving patients with no treatment options. PD has several derangements in neurotransmitter pathways (dopaminergic neurons in the nigrostriatal pathway, kynurenine pathway (KP), acetylcholine, α7 nicotinic receptor, and N-methyl-D-aspartate (NMDA) receptors) and rivastigmine is only partially effective as it only targets one pathway. Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, affects the pathophysiology of PDD in multiple ways. Both galantamine (α7 nicotinic receptor) and memantine (antagonist of the NMDA subtype of the glutamate receptor) are KYNA modulators. When used in combination, they target multiple pathways. While randomized controlled trials (RCTs) with each drug alone for PD have failed, the combination of galantamine and memantine has demonstrated a synergistic effect on cognitive enhancement in animal models. It has therapeutic potential that has not been adequately assessed, warranting future randomized controlled trials. In this review, we summarize the KYNA-centric model for PD pathophysiology and discuss how this treatment combination is promising in improving cognitive function in patients with PDD through its action on KYNA.

Dysregulated Coagulation in Parkinson's Disease.

Parkinson's disease (PD), a prevalent neurodegenerative disorder characterized by dopaminergic neuron degeneration and α-synuclein accumulation, has been increasingly associated with coagulation dysfunction. This review synthesizes emerging evidence linking dysregulated coagulation to PD pathophysiology. We examine the alterations in coagulation parameters, including elevated fibrinogen levels, impaired fibrinolysis, and platelet dysfunction, which collectively contribute to a hypercoagulable state in PD patients. Epidemiological studies have revealed a higher incidence of thrombotic events, such as deep vein thrombosis (DVT) and stroke, among PD patients, suggesting significant comorbidity between PD and coagulation disorders. This review explores the potential pathophysiological mechanisms underlying this association, focusing on the roles of inflammation and oxidative stress. Additionally, we discuss the limitations of current research and propose future directions. This comprehensive analysis underscores the importance of understanding the coagulation-neurodegeneration axis in PD, which may lead to novel diagnostic and therapeutic strategies for this debilitating condition.

Changes of upper-limb kinematics during practice of a redundant motor task in patients with Parkinson’s disease

The ability to learn novel motor skills is essential for patients with Parkinson’s disease (PD) to regain activities of daily living. However, the underlying mechanisms of motor learning in PD remain unclear. To identify motor features that are distinctively manifested in PD during motor learning, we quantified a rich set of variables reflecting various aspects of the learning process in a virtual throwing task. While the performance outcome improved similarly over 3 days of practice for both PD patients and age-matched controls, further analysis revealed distinct learning processes between the two groups. PD patients initially performed with a slow release velocity and gradually increased it as practice progressed, whereas the control group began with an unnecessarily rapid release velocity, which they later stabilized at a lower value. Performance characteristics related to the timing of ball release and the inter-release interval did not show significant group differences, although they were modulated across practice in both groups. After one week, both groups retained the performance outcomes and underlying kinematics developed over practice. This study underscores the importance of analyzing the multi-faceted learning process to characterize motor skill learning in PD. The findings may provide insights into PD pathophysiology and inform rehabilitation strategies.

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.

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>

A review of gut microbiota as a therapeutic approach for Parkinson’s disease

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder that affects the brain–gut axis, manifesting through both motor dysfunction and nonmotor symptoms. While several factors contribute to PD, the precise cause remains unknown. Research studies suggest that an altered gut microbiota (GM) plays a key role in PD pathophysiology. Gut dysbiosis compromises the integrity of the intestinal epithelium, increasing gastrointestinal permeability. This, in turn, activates the innate immune system, leading to systemic inflammation, whereas the adaptive immune system responds to bacterial proteins through cross-reactivity with human antigens. The altered GM promotes the accumulation of alpha-synuclein fibrils in the intestinal neural plexus, which are then transported to the central nervous system, driving the core pathological process of PD. This review focuses on the connection between gut dysbiosis, PD pathology, and current microbial-based therapeutic interventions. Furthermore, research into innovative approaches to modulate the GM and reinforce gut epithelial integrity is crucial to halting or slowing PD progression.

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.