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Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology

Parkinson’s disease (PD), the fastest-growing neurological disorder globally, has a complex etiology. A previous study by our group identified the p.G849D variant in neurexin 2 (NRXN2), encoding the synaptic protein, NRXN2α, as a possible causal variant of PD. Therefore, we aimed to perform function...

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Autores principales: Cuttler, Katelyn, Fortuin, Suereta, Müller-Nedebock, Amica Corda, Vlok, Maré, Cloete, Ruben, Bardien, Soraya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748613/
https://www.ncbi.nlm.nih.gov/pubmed/36533174
http://dx.doi.org/10.3389/fnagi.2022.1002777
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author Cuttler, Katelyn
Fortuin, Suereta
Müller-Nedebock, Amica Corda
Vlok, Maré
Cloete, Ruben
Bardien, Soraya
author_facet Cuttler, Katelyn
Fortuin, Suereta
Müller-Nedebock, Amica Corda
Vlok, Maré
Cloete, Ruben
Bardien, Soraya
author_sort Cuttler, Katelyn
collection PubMed
description Parkinson’s disease (PD), the fastest-growing neurological disorder globally, has a complex etiology. A previous study by our group identified the p.G849D variant in neurexin 2 (NRXN2), encoding the synaptic protein, NRXN2α, as a possible causal variant of PD. Therefore, we aimed to perform functional studies using proteomics in an attempt to understand the biological pathways affected by the variant. We hypothesized that this may reveal insight into the pathobiology of PD. Wild-type and mutant NRXN2α plasmids were transfected into SH-SY5Y cells. Thereafter, total protein was extracted and prepared for mass spectrometry using a Thermo Scientific Fusion mass spectrometer equipped with a Nanospray Flex ionization source. The data were then interrogated against the UniProt H. sapiens database and afterward, pathway and enrichment analyses were performed using in silico tools. Overexpression of the wild-type protein led to the enrichment of proteins involved in neurodegenerative diseases, while overexpression of the mutant protein led to the decline of proteins involved in ribosomal functioning. Thus, we concluded that the wild-type NRXN2α may be involved in pathways related to the development of neurodegenerative disorders, and that biological processes related to the ribosome, transcription, and tRNA, specifically at the synapse, could be an important mechanism in PD. Future studies targeting translation at the synapse in PD could therefore provide further information on the pathobiology of the disease.
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spelling pubmed-97486132022-12-15 Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology Cuttler, Katelyn Fortuin, Suereta Müller-Nedebock, Amica Corda Vlok, Maré Cloete, Ruben Bardien, Soraya Front Aging Neurosci Aging Neuroscience Parkinson’s disease (PD), the fastest-growing neurological disorder globally, has a complex etiology. A previous study by our group identified the p.G849D variant in neurexin 2 (NRXN2), encoding the synaptic protein, NRXN2α, as a possible causal variant of PD. Therefore, we aimed to perform functional studies using proteomics in an attempt to understand the biological pathways affected by the variant. We hypothesized that this may reveal insight into the pathobiology of PD. Wild-type and mutant NRXN2α plasmids were transfected into SH-SY5Y cells. Thereafter, total protein was extracted and prepared for mass spectrometry using a Thermo Scientific Fusion mass spectrometer equipped with a Nanospray Flex ionization source. The data were then interrogated against the UniProt H. sapiens database and afterward, pathway and enrichment analyses were performed using in silico tools. Overexpression of the wild-type protein led to the enrichment of proteins involved in neurodegenerative diseases, while overexpression of the mutant protein led to the decline of proteins involved in ribosomal functioning. Thus, we concluded that the wild-type NRXN2α may be involved in pathways related to the development of neurodegenerative disorders, and that biological processes related to the ribosome, transcription, and tRNA, specifically at the synapse, could be an important mechanism in PD. Future studies targeting translation at the synapse in PD could therefore provide further information on the pathobiology of the disease. Frontiers Media S.A. 2022-11-30 /pmc/articles/PMC9748613/ /pubmed/36533174 http://dx.doi.org/10.3389/fnagi.2022.1002777 Text en Copyright © 2022 Cuttler, Fortuin, Müller-Nedebock, Vlok, Cloete and Bardien. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging Neuroscience
Cuttler, Katelyn
Fortuin, Suereta
Müller-Nedebock, Amica Corda
Vlok, Maré
Cloete, Ruben
Bardien, Soraya
Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title_full Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title_fullStr Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title_full_unstemmed Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title_short Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology
title_sort proteomics analysis of the p.g849d variant in neurexin 2 alpha may reveal insight into parkinson’s disease pathobiology
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748613/
https://www.ncbi.nlm.nih.gov/pubmed/36533174
http://dx.doi.org/10.3389/fnagi.2022.1002777
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