A Gene Variant, Parkinson’s Disease and the Synapse

By Dr Maré Vlok, Founder of Trace Labs

A single spelling change in one gene, found in a South African family affected by Parkinson’s disease. What does it do to the cell?

Parkinson’s and the Synapse

Parkinson’s disease is the fastest-growing neurological condition in the world. It is best known for tremor, stiffness and slowed movement, but it also affects sleep, mood, smell and thinking. Most cases have no single genetic cause, but studying families in which the disease runs can reveal which biological processes go wrong.

Synapses, the junctions where nerve cells pass signals to each other, are a growing focus. Neurexins are proteins that help build and maintain synapses, and NRXN2α is one of them.

What We Did

Prof Soraya Bardien’s group at Stellenbosch University had earlier identified a variant called p.G849D in the NRXN2 gene in a South African family with Parkinson’s disease, and proposed it as a possible cause. In this follow-up, led by Katelyn Cuttler, the team made human neuroblastoma cells (SH-SY5Y, a widely used model for nerve cells) produce either the normal or the variant form of NRXN2α, and compared their proteins with control cells.

My Part in the Study

The protein extraction and mass spectrometry were carried out at Stellenbosch University’s Central Analytical Facility, on a Thermo Scientific Fusion mass spectrometer. My role covered developing the methods, training the students on sample preparation, setting up the instruments, acquiring and processing the data, writing the data reports, and reviewing the manuscript before publication.

What We Found

The normal protein: cells making extra normal NRXN2α showed an increase in proteins linked to neurodegenerative diseases, including Parkinson’s, Alzheimer’s and Huntington’s, mostly involved in mitochondria and lysosomes, the cell’s power plants and recycling centres.
The variant: cells making the variant form had fewer ribosome-related proteins. Ribosomes are the machinery that builds proteins, and at synapses, local protein building is essential for healthy communication between nerve cells.

What This Means

The results suggest NRXN2α is connected to pathways already implicated in neurodegeneration, and that disrupted protein building at the synapse could be one way the variant contributes to disease. The authors recommend future work on translation at the synapse.

This was an exploratory study in a cell line, and the findings need to be confirmed in other models. But it shows how proteomics can turn a single gene variant into a set of testable biological leads. The data are publicly available in the PRIDE database (PXD036636) for other researchers to use.