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, NRXN2 alpha, 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 NRXN2 alpha 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 NRXN2 alpha 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.

Automated summary

This study investigated the potential role of NRXN2 alpha in Parkinson's disease, finding that the wild-type NRXN2 alpha may be involved in pathways related to neurodegenerative disorders, while the mutant NRXN2 alpha may affect proteins involved in ribosomal functioning. These findings suggest that translation at the synapse, as well as biological processes related to the ribosome, transcription, and tRNA, may play an important role in the pathobiology of PD.