Parkinson's disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been ...fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish,
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, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as α-Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes.
Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, ...impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system.
The homeostasis of iron is vital to human health, and iron dyshomeostasis can lead to various disorders. Iron homeostasis is maintained by iron regulatory proteins (IRP1 and IRP2) and the ...iron-responsive element (IRE) signaling pathway. IRPs can bind to RNA stem-loops containing an IRE in the untranslated region (UTR) to manipulate translation of target mRNA. However, iron can bind to IRPs, leading to the dissociation of IRPs from the IRE and altered translation of target transcripts. Recently an IRE is found in the 5'-UTR of amyloid precursor protein (APP) and α-synuclein (α-Syn) transcripts. The levels of α-Syn, APP and amyloid β-peptide (Aβ) as well as protein aggregation can be down-regulated by IRPs but are up-regulated in the presence of iron accumulation. Therefore, inhibition of the IRE-modulated expression of APP and α-Syn or chelation of iron in patient's brains has therapeutic significance to human neurodegenerative diseases. Currently, new pre-drug IRE inhibitors with therapeutic effects have been identified and are at different stages of clinical trials for human neurodegenerative diseases. Although some promising drug candidates of chemical IRE inhibitors and iron-chelating agents have been identified and are being validated in clinical trials for neurodegenerative diseases, future studies are expected to further establish the clinical efficacy and safety of IRE inhibitors and iron-chelating agents in patients with neurodegenerative diseases.
Role of MicroRNAs in Parkinson's Disease Goh, Suh Yee; Chao, Yin Xia; Dheen, Shaikali Thameem ...
International journal of molecular sciences,
11/2019, Letnik:
20, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Parkinson's disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in ...1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood-brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.
Several studies investigating the effect of COVID-19 on individuals with Parkinson's disease have suggested that parkinsonian symptoms worsened among those who were infected, that those with more ...advanced Parkinson's disease were at increased risk of pulmonary compromise, that hospitalised patients with Parkinson's disease and COVID-19 appeared to have a heightened mortality rate, and that patients with Parkinson's disease showed more stress, depressive symptoms, and anxiety during the lockdown period than before this period.1 A case report linking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with new-onset Parkinson's disease has led to an increased awareness of this potential association and also its underlying biological plausibility.2 Amid the pandemic, several clinical safety and proof-of-concept trials have taken small steps towards identifying disease-modifying therapies. A multicentre, randomised, double-blind study in patients with Parkinson's disease and more than 2 h off time per day compared an effective dose of apomorphine sublingual film individually titrated to 10–35 mg with a placebo (54 vs 55 patients).5 There was a significantly better improvement in the Movement Disorder Society-Unified Parkinson Disease Rating Scale motor scores (from pre-dose to 30 min post-dose) at week 12 in participants receiving apomorphine than in those receiving placebo. 31% of participants who were on the drug reported mild-to-moderate oropharyngeal side-effects, with 17% discontinuing the treatment. In essence, the application of exome sequencing in a collective large number of patients with dystonia improves diagnosis, facilitates genotype–phenotype correlation, potentially guides genetic testing, and improves the clinical management of patients with dystonia.
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