Amelioration of Alpha-Synuclein in Parkinson's Disease through potentiated protein-protein interactions

10.18258/8102 ◽  
2016 ◽  
Author(s):  
Jeremiah Pate Jeremiah Pate
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Interactions ◽  
Alpha Synuclein ◽  
Protein Protein Interactions

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 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.

scholarly journals Deciphering the activation of the E3 ubiquitin ligase parkin

2014 ◽  
Vol 70 (a1) ◽  
pp. C836-C836
Author(s):  
Véronique Sauvé ◽  
Kalle Gehring
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Protein Interactions ◽  
E3 Ubiquitin Ligase ◽  
Intramolecular Interactions ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Catalytic Cysteine ◽  
Insight Into

Parkin is an E3 ubiquitin ligase responsible for some autosomal recessive forms of Parkinson's disease. Even though parkin is a RING-type E3 ligase, it uses a hybrid RING/HECT mechanism for its activity. The crystal structures of full-length and the RING0-RING1-In-Between-RING-RING2 module of parkin reveal a conformation of parkin in which its E2 binding site is too far from its catalytic cysteine for the transfer of ubiquitin [1]. Many intramolecular interactions occur between the different RING domains, as well as with a repressor element, which, with RING0, are unique to parkin. Mutations of residues involved in those interactions lead to an increase of parkin activity. This suggests that parkin adopts an auto-inhibited state in basal conditions. Therefore, under stress-response conditions, parkin needs to undergo molecular rearrangements, modulated by post-translational modification and/or interactions with other proteins, to become active. The phosphorylation of serine 65 in the Ubl domain of parkin by Pink1, a kinase also found mutated in some Parkinson's patient, was shown to increase the activity of parkin. Recent publications have demonstrated that ubiquitin is also phosphorylated by Pink1 and, furthermore, that phosphorylated ubiquitin could activate parkin [2,3]. We have used different techniques of structural biology and protein-protein interactions to further characterize the interaction of phosphorylated ubiquitin with parkin. This work provides insight into the mechanism of activation of parkin and that causes Parkinson's disease.

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