scholarly journals Pathways to Parkinson’s disease: a spotlight on 14-3-3 proteins

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
E. Giusto ◽  
T. A. Yacoubian ◽  
E. Greggio ◽  
L. Civiero
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Interactions ◽  
Lewy Bodies ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
Neuroprotective Effects ◽  
The Central Nervous System ◽  
Acidic Proteins ◽  
Target Binding

Abstract14-3-3s represent a family of highly conserved 30 kDa acidic proteins. 14-3-3s recognize and bind specific phospho-sequences on client partners and operate as molecular hubs to regulate their activity, localization, folding, degradation, and protein–protein interactions. 14-3-3s are also associated with the pathogenesis of several diseases, among which Parkinson’s disease (PD). 14-3-3s are found within Lewy bodies (LBs) in PD patients, and their neuroprotective effects have been demonstrated in several animal models of PD. Notably, 14-3-3s interact with some of the major proteins known to be involved in the pathogenesis of PD. Here we first provide a detailed overview of the molecular composition and structural features of 14-3-3s, laying significant emphasis on their peculiar target-binding mechanisms. We then briefly describe the implication of 14-3-3s in the central nervous system and focus on their interaction with LRRK2, α-Synuclein, and Parkin, three of the major players in PD onset and progression. We finally discuss how different types of small molecules may interfere with 14-3-3s interactome, thus representing a valid strategy in the future of drug discovery.

Protein interaction studies for understanding the tremor pathway in Parkinson’s disease.

2020 ◽  
Vol 19 ◽  
Author(s):  
Nitu Dogra ◽  
Ruchi Jakhmola Mani ◽  
Deepshikha Pande Katare
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Interaction Network ◽  
Literature Mining ◽  
Protein Protein Interactions ◽  
Calcium Ion Channels ◽  
Progression Of Disease ◽  
Different Sources

Background: Tremor is one of the most noticeable features, which occurs during the early stages of Parkinson’s disease (PD). It is one of the major pathological hallmarks and does not have any interpreted mechanism. In this study we have framed a hypothesis and deciphered protein-protein interactions between the proteins involved in impairment in sodium and calcium ion channels and thus cause synaptic plasticity leading to a tremor. Methods: Literature mining for retrieval of proteins was done using Science Direct, PubMed Central, SciELO and JSTOR databases. A well thought approach was used and a list of differentially expressed proteins in PD was collected from different sources. A total of 71 proteins were retrieved and a protein interaction network was constructed between them by using Cytoscape.v.3.7. The network was further analysed using BiNGO plugin for retrieval of overrepresented biological processes in Tremor-PD datasets. Hub nodes were also generated in the network. Results: The Tremor-PD pathway was deciphered which demonstrates the cascade of protein interactions that might lead to tremors in PD. Major proteins involved were LRRK2, TUBA1A, TRAF6, HSPA5, ADORA2A, DRD1, DRD2, SNCA, ADCY5, TH etc. Conclusion: In the current study it is predicted that ADORA2A and DRD1/DRD2 are equally contributing to the progression of disease by inhibiting the activity of adenylyl cyclase and thereby increases the permeability of the blood brain barrier causing an influx of neurotransmitters and together they alter the level of dopamine in the brain which eventually leads to tremor.

scholarly journals GPR6 Structural Insights: Homology Model Construction and Docking Studies

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 725
Author(s):  
Israa H. Isawi ◽  
Paula Morales ◽  
Noori Sotudeh ◽  
Dow P. Hurst ◽  
Diane L. Lynch ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Homology Model ◽  
Structural Features ◽  
Docking Studies ◽  
Computational Techniques ◽  
Wide Range ◽  
Biological Target ◽  
The Central Nervous System ◽  
Key Residues

GPR6 is an orphan G protein-coupled receptor that has been associated with the cannabinoid family because of its recognition of a sub-set of cannabinoid ligands. The high abundance of GPR6 in the central nervous system, along with high constitutive activity and a link to several neurodegenerative diseases make GPR6 a promising biological target. In fact, diverse research groups have demonstrated that GPR6 represents a possible target for the treatment of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Several patents have claimed the use of a wide range of pyrazine derivatives as GPR6 inverse agonists for the treatment of Parkinson’s disease symptoms and other dyskinesia syndromes. However, the full pharmacological importance of GPR6 has not yet been fully explored due to the lack of high potency, readily available ligands targeting GPR6. The long-term goal of the present study is to develop such ligands. In this paper, we describe our initial steps towards this goal. A human GPR6 homology model was constructed using a suite of computational techniques. This model permitted the identification of unique GPR6 structural features and the exploration of the GPR6 binding crevice. A subset of patented pyrazine analogs were docked in the resultant GPR6 inactive state model to validate the model, rationalize the structure-activity relationships from the reported patents and identify the key residues in the binding crevice for ligand recognition. We will take this structural knowledge into the next phase of GPR6 project, in which scaffold hopping will be used to design new GPR6 ligands.

scholarly journals Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 4766 ◽  
Author(s):  
Giovanni Schepici ◽  
Serena Silvestro ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Antioxidant Properties ◽  
Lewy Bodies ◽  
Experimental Models ◽  
Substantia Nigra Pars Compacta ◽  
Dopamine Depletion ◽  
Neuroprotective Effects ◽  
Cytoplasmic Inclusions

Parkinson’s Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD.

scholarly journals C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Abdelrahman Ibrahim Abushouk ◽  
Ahmed Negida ◽  
Rasha Abdelsalam Elshenawy ◽  
Hossam Zein ◽  
Ali M. Hammad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Experimental Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Current Evidence ◽  
Future Research ◽  
Neuroprotective Effects ◽  
Human Trial

Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area.

Immunotherapies for Parkinson’s disease: Progression of Clinical Development

2021 ◽  
Vol 20 ◽  
Author(s):  
Jet Shee Teng ◽  
Yin Yin Ooi ◽  
Soi Moi Chye ◽  
Anna Pick Kiong Ling ◽  
Rhun Yian Koh
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Clinical Development ◽  
Positive Outcomes ◽  
Disease Treatment ◽  
New Approach ◽  
Resting Tremor ◽  
The Central Nervous System

: Parkinson’s disease is a common neurodegenerative disease affecting the movement and wellbeing of most elderlies. The manifestations of Parkinson’s disease often include resting tremor, stiffness, bradykinesia and muscular rigidity. The typical hallmark of Parkinson’s disease is the destruction of neurons in the substantia nigra and the presence of Lewy bodies in different compartments of the central nervous system. Due to various limitations to the currently available treatments, immunotherapies have emerged to be the new approach to Parkinson’s disease treatment. This approach shows some positive outcomes on the efficacy in removing the aggregated species of alpha-synuclein, which is believed to be one of the causes of Parkinson’s disease. In this review, an overview of how alpha-synuclein contributes to Parkinson’s disease and the effects of a few new immunotherapeutic treatments, including BIIB054 (cinpanemab), MEDI1341, AFFITOPE and PRX002 (prasinezumab) that are currently under clinical development, will be discussed.

scholarly journals Mechanistic Insights Expatiating the Redox-Active-Metal-Mediated Neuronal Degeneration in Parkinson’s Disease

2022 ◽  
Vol 23 (2) ◽  
pp. 678
Author(s):  
Tapan Behl ◽  
Piyush Madaan ◽  
Aayush Sehgal ◽  
Sukhbir Singh ◽  
Md Khalid Anwer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuronal Degeneration ◽  
Lewy Bodies ◽  
Ubiquitin Proteasome System ◽  
Substantia Nigra Pars Compacta ◽  
Ros Generation ◽  
Redox Active ◽  
Ubiquitin Proteasome ◽  
The Central Nervous System

Parkinson’s disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), autophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochondrial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations, for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and conveyance of oxygen (O2). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood–brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein aggregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD.

scholarly journals GM1 Is Cytoprotective in GPR37-Expressing Cells and Downregulates Signaling

2021 ◽  
Vol 22 (23) ◽  
pp. 12859
Author(s):  
Ellen Hertz ◽  
Marcus Saarinen ◽  
Per Svenningsson
Keyword(s):  
Protein Interactions ◽  
Drug Target ◽  
Protective Effects ◽  
Protein Protein Interactions ◽  
Neuroprotective Effects ◽  
The Central Nervous System ◽  
Intracellular Changes ◽  
The Many ◽  
G Protein Coupled ◽  
Orphan Gpcr

G-protein-coupled receptors (GPCRs) are commonly pharmacologically modulated due to their ability to translate extracellular events to intracellular changes. Previously, studies have mostly focused on protein–protein interactions, but the focus has now expanded also to protein–lipid connections. GM1, a brain-expressed ganglioside known for neuroprotective effects, and GPR37, an orphan GPCR often reported as a potential drug target for diseases in the central nervous system, have been shown to form a complex. In this study, we looked into the functional effects. Endogenous GM1 was downregulated when stably overexpressing GPR37 in N2a cells (N2aGPR37-eGFP). However, exogenous GM1 specifically rescued N2aGPR37-eGFP from toxicity induced by the neurotoxin MPP+. The treatment did not alter transcription levels of GPR37 or the enzyme responsible for GM1 production, both potential mechanisms for the effect. However, GM1 treatment inhibited cAMP-dependent signaling from GPR37, here reported as potentially consecutively active, possibly contributing to the protective effects. We propose an interplay between GPR37 and GM1 as one of the many cytoprotective effects reported for GM1.

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