A sticky situation: Aberrant protein–protein interactions in Parkinson’s disease

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.

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Protein-Protein Interactions in Alpha-Synuclein Biogenesis: New Potential Targets in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.00072 ◽

2020 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Sarah M. Hernandez ◽

Elena B. Tikhonova ◽

Andrey L. Karamyshev

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Interactions ◽

Alpha Synuclein ◽

Protein Protein Interactions

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

npj Parkinson s Disease ◽

10.1038/s41531-021-00230-6 ◽

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.

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Deciphering the activation of the E3 ubiquitin ligase parkin

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314091633 ◽

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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Cascading from SARS-CoV-2 to Parkinson’s Disease through Protein-Protein Interactions

Viruses ◽

10.3390/v13050897 ◽

2021 ◽

Vol 13 (5) ◽

pp. 897

Author(s):

Ernesto Estrada

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Interactions ◽

Molecular Level ◽

Direct Consequence ◽

Viral Proteins ◽

Clinical Findings ◽

Post Translational Modification ◽

Host Proteins ◽

Bioinformatic Tools

Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson’s disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD, some hypotheses have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients, in general, and for the PD cases reported, in particular. Given the importance of this potential connection, we present here a molecular-level mechanistic hypothesis that explains well these findings and will serve to explore the potential CNS damage in COVID-19 patients. The model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Our hypothesis is supported by finding 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. The molecular-level mechanistic hypothesis presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

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Carnoquinolines Target Copper Dyshomeostasis, Aberrant Protein–Protein Interactions, and Oxidative Stress

Chemistry - A European Journal ◽

10.1002/chem.202001591 ◽

2020 ◽

Vol 26 (70) ◽

pp. 16690-16705

Author(s):

Francesco Bellia ◽

Giuseppa Ida Grasso ◽

Ikhlas Mohamed Mohamud Ahmed ◽

Valentina Oliveri ◽

Graziella Vecchio

Keyword(s):

Oxidative Stress ◽

Protein Interactions ◽

Protein Protein Interactions ◽

Aberrant Protein ◽

Copper Dyshomeostasis ◽

And Oxidative Stress

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Cascading from SARS-CoV-2 to Parkinson's Disease through Protein-Protein Interactions

10.21203/rs.3.rs-147776/v1 ◽

2021 ◽

Author(s):

Ernesto Estrada

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Interactions ◽

Molecular Level ◽

Direct Consequence ◽

Viral Proteins ◽

Clinical Findings ◽

Post Translational Modification ◽

Host Proteins ◽

Bioinformatic Tools

Abstract Background : Extensive extrapulmonary damages in a dozen of organs/systems, including the central nervous system (CNS), are reported in patients of the coronavirus disease 2019 (COVID-19). Three cases of Parkinson's disease (PD) have been reported as a direct consequence of COVID-19. In spite of the scarce data for establishing a definitive link between COVID-19 and PD some hypothesis have been proposed to explain the cases reported. They, however, do not fit well with the clinical findings reported for COVID-19 patients in general and for the PD cases reported in particular. Given the importance of this potential connection we present here a molecular-level mechanism that explain well these findings and will serve to explore the potential CNS damage in COVID-19 patients. Methods : A model explaining the cascade effects from COVID-19 to CNS is developed by using bioinformatic tools. It includes the post-translational modification of host proteins in the lungs by viral proteins, the transport of modified host proteins via exosomes out the lungs, and the disruption of protein-protein interaction in the CNS by these modified host proteins. Results : We found 44 proteins significantly expressed in the CNS which are associated with PD and whose interactions can be perturbed by 24 host proteins significantly expressed in the lungs. These 24 perturbators are found to interact with viral proteins and to form part of the cargoes of exosomes in human tissues. The joint set of perturbators and PD-vulnerable proteins form a tightly connected network with significantly more connections than expected by selecting a random cluster of proteins of similar size from the human proteome. Conclusions : The molecular-level mechanism presented here provides several routes for the cascading of effects from the lungs of COVID-19 patients to PD. In particular, the disruption of autophagy/ubiquitination processes appears as an important mechanism that triggers the generation of large amounts of exosomes containing perturbators in their cargo, which would insult several PD-vulnerable proteins, potentially triggering Parkinsonism in COVID-19 patients.

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RNA pull-down-Confocal Nanoscanning (RP-CONA) detects quercetin as pri-miR-7/HuR interaction inhibitor that decreases α-Synuclein levels

10.1101/2021.01.01.425030 ◽

2021 ◽

Author(s):

Siran Zhu ◽

Saul Rooney ◽

Nhan T. Pham ◽

Joanna Koszela ◽

David Kelly ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Small Molecules ◽

Protein Interaction ◽

Protein Interactions ◽

Eukaryotic Cell ◽

Therapeutic Approaches ◽

Cell Extracts ◽

Terminal Loop ◽

Screening Platform

ABSTRACTRNA-protein interactions are central to all gene expression processes and contribute to variety of human diseases. Therapeutic approaches targeting RNA-protein interactions have shown promising effects on some diseases that are previously regarded as ‘incurable’. Here we developed a fluorescent on-bead screening platform: RNA pull-down-Confocal Nanoscanning (RP-CONA), to identify RNA-protein interaction modulators in eukaryotic cell extracts. Using RP-CONA, we identified small molecules that disrupt the interaction between HuR, an inhibitor of brain-enriched miR-7 biogenesis, and the conserved terminal loop of pri-miR-7-1. Importantly, miR-7’s primary target is an mRNA of α-Synuclein, which contributes to aetiology of Parkinson’s disease. Our method identified a natural product quercetin as a molecule able to upregulate cellular miR-7 levels and downregulate the expression of α-Synuclein. This opens up new therapeutic avenues towards treatment of Parkinson’s disease as well as provides novel methodology to search for RNA-protein interaction modulators.

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Synaptojanin 1 Mutation in Parkinson’s Disease Brings Further Insight into the Neuropathological Mechanisms

BioMed Research International ◽

10.1155/2014/289728 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 34

Author(s):

Valérie Drouet ◽

Suzanne Lesage

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Interactions ◽

Synaptic Activity ◽

Atypical Symptoms ◽

Rich Domain ◽

New Genes ◽

Phosphoinositide Phosphatase ◽

Synaptojanin 1 ◽

Insight Into

Synaptojanin 1 (SYNJ1) is a phosphoinositide phosphatase highly expressed in nerve terminals. Its two phosphatase domains dephosphorylate phosphoinositides present in membranes, while its proline-rich domain directs protein-protein interactions with synaptic components, leading to efficient recycling of synaptic vesicles in neurons. Triplication of SYNJ1 in Down’s syndrome is responsible for higher level of phosphoinositides, enlarged endosomes, and learning deficits. SYNJ1 downregulation in Alzheimer’s disease models is protective towards amyloid-beta peptide (Aβ) toxicity. One missense mutation in one of SYNJ1 functional domains was recently incriminated in an autosomal recessive form of early-onset Parkinson’s disease (PD). In the third decade of life, these patients develop progressive Parkinsonism with bradykinesia, dystonia, and variable atypical symptoms such as cognitive decline, seizures, and eyelid apraxia. The identification of this new gene, together with the fact that most of the known PD proteins play a role in synaptic vesicle recycling and lipid metabolism, points out that synaptic maintenance is a key player in PD pathological mechanisms. Studying PD genes as a network regulating synaptic activity could bring insight into understanding the neuropathological processes of PD and help identify new genes at fault in this devastating disorder.

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