Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

Junqueira, Stella Célio; Centeno, Eduarda Gervini Zampieri; Wilkinson, Kevin A.; Cimarosti, Helena

doi:10.1016/j.bbadis.2018.10.025

Cited by 36 publications

(22 citation statements)

References 49 publications

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“…“Cellular protein modification,” “Nucleic acid binding transcription factor activity,” “Cell death,” “Catabolic process,” were overrepresented among the biological processes affected. Cellular protein modifications such as phosphorylation, ubiquitination, truncation, acetylation, nitration, and sumoylation of PD‐linked proteins have emerged as important modulators of pathogenic mechanisms in PD 71,72 . Transcription factor changes are also of particular interest, as they indicate that there is not only misexpression at the mRNA translation level by miRNA deregulation, but that there exists a second wave of en masse deregulation involving transcription‐wide changes.…”

Section: Discussionmentioning

confidence: 99%

Validation of differentially expressed brain‐enriched microRNAs in the plasma of PD patients

Ravanidis

Bougea

Papagiannakis

et al. 2020

Ann Clin Transl Neurol

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Objective There is a pressing need to identify and validate, minimally invasive, molecular biomarkers that will complement current practices and increase the diagnostic accuracy in Parkinson’s disease (PD). Brain‐enriched miRNAs regulate all aspects of neuron development and function; importantly, they are secreted by neurons in amounts that can be readily detected in the plasma. Τhe aim of the present study was to validate a set of previously identified brain‐enriched miRNAs with diagnostic potential for idiopathic PD and recognize the molecular pathways affected by these deregulated miRNAs. Methods RT‐qPCR was performed in the plasma of 92 healthy controls and 108 idiopathic PD subjects. Statistical and in silico analyses were used to validate deregulated miRNAs and pathways in PD, respectively. Results miR‐22‐3p, miR‐124‐3p, miR‐136‐3p, miR‐154‐5p, and miR‐323a‐3p levels were found to be differentially expressed between healthy controls and PD patients. miR‐330‐5p, miR‐433‐3p, and miR‐495‐3p levels were overall higher in male subjects. Most of these miRNAs are clustered at Chr14q32 displaying CREB1, CEBPB, and MAZ transcription factor binding sites. Gene Ontology annotation analysis of deregulated miRNA targets revealed that “Protein modification,” “Transcription factor activity,” and “Cell death” terms were over‐represented. Kyoto Encyclopedia of Genes and Genome analysis revealed that “Long‐term depression,” “TGF‐beta signaling,” and “FoxO signaling” pathways were significantly affected. Interpretation We validated a panel of brain‐enriched miRNAs that can be used along with other measures for the detection of PD, revealed molecular pathways targeted by these deregulated miRNAs, and identified upstream transcription factors that may be directly implicated in PD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Validation of differentially expressed brain‐enriched microRNAs in the plasma of PD patients

Ravanidis

Bougea

Papagiannakis

et al. 2020

Ann Clin Transl Neurol

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“…We and others have shown that SUMOylation is part of an endogenous neuroprotective response in ischemic conditions [8][9][10][11][12]. Furthermore, several proteins implicated in ischemia [13], and neurodegenerative disorders [14], such as Alzheimer's [15][16][17] and Parkinson's diseases [18,19], are SUMO targets, and SUMOylation has been linked to agerelated processes [20,21]. As a result, SUMOylation may represent an attractive therapeutic target in several disorders.…”

Section: Introductionmentioning

confidence: 99%

Guanosine modulates SUMO2/3-ylation in neurons and astrocytes via adenosine receptors

Zanella

Tasca

Henley

et al. 2020

Purinergic Signalling

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SUMOylation is a post-translational modification (PTM) whereby members of the Small Ubiquitin-like MOdifier (SUMO) family of proteins are conjugated to lysine residues in target proteins. SUMOylation has been implicated in a wide range of physiological and pathological processes, and much attention has been given to its role in neurodegenerative conditions. Due to its reported role in neuroprotection, pharmacological modulation of SUMOylation represents an attractive potential therapeutic strategy in a number of different brain disorders. However, very few compounds that target the SUMOylation pathway have been identified. Guanosine is an endogenous nucleoside with important neuromodulatory and neuroprotective effects. Experimental evidence has shown that guanosine can modulate different intracellular pathways, including PTMs. In the present study we examined whether guanosine alters global protein SUMOylation. Primary cortical neurons and astrocytes were treated with guanosine at 1, 10, 100, 300, or 500 μM at four time points, 1, 6, 24, or 48 h. We show that guanosine increases global SUMO2/3-ylation in neurons and astrocytes at 1 h at concentrations above 10 μM. The molecular mechanisms involved in this effect were evaluated in neurons. The guanosine-induced increase in global SUMO2/3-ylation was still observed in the presence of dipyridamole, which prevents guanosine internalization, demonstrating an extracellular guanosine-induced effect. Furthermore, the A1 adenosine receptor antagonist DPCPX abolished the guanosine-induced increase in SUMO2/3-ylation. The A2A adenosine receptor antagonist ZM241385 increased SUMOylation per se, but did not alter guanosine-induced SUMOylation, suggesting that guanosine may modulate SUMO2/3-ylation through an A1-A2A receptor interaction. Taken together, this is the first report to show guanosine as a SUMO2/3-ylation enhancer in astrocytes and neurons.

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“…'Cellular protein modi cation', 'Nucleic acid binding transcription factor activity', 'Cell death', 'Catabolic process', were overrepresented among the biological processes affected. Cellular protein modi cations such as phosphorylation, ubiquitination, truncation, acetylation, nitration and sumoylation of PD-linked proteins have emerged as important modulators of pathogenic mechanisms in PD [61,62]. Transcription factor changes are also of particular interest, as they indicate that there is not only misexpression at the mRNA translation level by miRNA deregulation, but that there exists a second wave of en masse deregulation involving transcription-wide changes.…”

Section: Discussionmentioning

confidence: 99%

Validation of Differentially Expressed Brain-Enriched microRNAs in the Plasma of Parkinson’s Disease Patients

Ravanidis¹,

Bougea

Papagiannakis

et al. 2020

Preprint

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Background There is a pressing need to identify and validate, minimally invasive, molecular biomarkers that will complement current practices and increase the diagnostic accuracy in Parkinson’s disease (PD). Brain-enriched miRNAs regulate all aspects of neuron development and function; importantly, they are secreted by neurons in amounts that can be readily detected in the plasma. Τhe aim of the present study was to validate a set of previously identified brain-enriched miRNAs with a diagnostic potential for idiopathic PD and recognize the molecular pathways affected by these deregulated miRNAs.Methods RT-qPCR was performed in the plasma of 92 healthy controls and 108 idiopathic PD subjects. Statistical and in silico analyses were used to validate deregulated miRNAs and pathways in PD, respectively.Results miR-22-3p, miR-124-3p, miR-136-3p, miR-154-5p and miR-323a-3p levels were found to be differentially expressed between healthy controls and PD patients. miR-330-5p, miR-433-3p and miR-495-3p levels were overall higher in male subjects. Most of these miRNAs are clustered at Chr14q32 displaying CREB1, CEBPB, and MAZ transcription factor binding sites. Gene Ontology (GO) annotation analysis of deregulated miRNA targets revealed that ‘Protein modification’, ‘Transcription factor activity’ and ‘Cell death’ terms were over-represented. Kyoto Encyclopedia of Genes and Genome (KEGG) analysis revealed that ‘Long-term depression’, ‘TGF-beta signaling’, and ‘FoxO signaling’ pathways were significantly affected.Conclusions We validated a panel of brain-enriched miRNAs that can be used along with other measures for the detection of PD, revealed molecular pathways targeted by these deregulated miRNAs, and identified upstream transcription factors that may be directly implicated in their regulation and thereafter PD pathogenesis.

show abstract

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination

Cited by 36 publications

References 49 publications

Validation of differentially expressed brain‐enriched microRNAs in the plasma of PD patients

Validation of differentially expressed brain‐enriched microRNAs in the plasma of PD patients

Guanosine modulates SUMO2/3-ylation in neurons and astrocytes via adenosine receptors

Validation of Differentially Expressed Brain-Enriched microRNAs in the Plasma of Parkinson’s Disease Patients

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