Exploring the Role of Neurexin 2 Alpha Variant in Parkinson’s Disease Pathobiology

Published on November 30, 2022

Imagine unraveling the secrets of Parkinson’s disease by studying a specific variant, p.G849D, in the neurexin 2 alpha protein. This variant could hold valuable insights into the biological pathways underlying the disease. In this study, scientists transfected wild-type and mutant NRXN2α plasmids into SH-SY5Y cells, extracting total protein for mass spectrometry analysis. The results were then compared to a human protein database to identify affected pathways. Interestingly, overexpression of the wild-type protein led to an enrichment of proteins linked to neurodegenerative diseases, while overexpression of the mutant protein showed a decline in ribosomal functioning proteins. These findings suggest that wild-type NRXN2α may play a role in neurodegenerative disorders’ development, and that ribosome-related processes at the synapse could be crucial in Parkinson’s disease. By delving deeper into translation processes at the synapse, future studies could shed further light on the disease’s pathobiology. Discover more about this fascinating research by exploring the article!

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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