Understanding Parkinson's Disease through gene silencing

Parkinson's Disease (PD) is a condition that affects the brain and makes it harder for people to control their movements. It usually starts slowly and gets worse over time. It’s a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the brain. By 2050, the number of people with Parkinson’s is projected worldwide to exceed 25.2 million, representing a 112% increase from 2021. The cause of neurodegeneration in Parkinson's remains unclear, though it is believed to result from the interplay of genetic, ageing and environmental factors. Among the genes involved in this disease, the ATP13A2 gene encodes a protein involved in the transport of ions in the cells. The loss of functionality of this gene is associated with a juvenile-onset form of PD. In a pilot study recently published in npj Parkinson’s disease, researchers from the University of Bordeaux and the University of Poitiers aimed to understand the role of ATP13A2 dysfunction in PD by downregulating its expression in non-human primates. They performed X-ray Ffluorescence experiments on I18, the Microfocus Spectroscopy beamline at Diamond, to measure metal levels in brain tissue from macaques. 

To understand the role of a gene in a living being, scientists can do several things: perform genetics studies on a population to find subjects which have a mutation of the gene of interest and study its effect on the cells or use genetic tools to modify its expression level in an animal or plants. Increasing or reducing a gene’s expression can increase or reduce the number of proteins in the cells. Nowadays, by using neutralised and modified viruses, scientists can modify the expression of a gene and analyse the evolution in vivo. To aid the effort of understanding the conditions that trigger PD's emergence it is essential to have a model that allows us to analyse the different mechanisms that lead to the loss of neurons in the brain. 

For this study, the research team infected the brains of macaques, which resulted in a 95% loss of expression of the ATP13A2 gene. Their goal was to see if this technique can induce early signs of Parkinson’s Disease in non-human primates. Five months later, they analysed the differences between the brains of primates with supressed ATP13A2 activity (injected) and control (non-injected) primates of the same age. 

They demonstrated a 30% loss of neuron cells in the most affected region of the injected animals. To further investigate what the effect of the modified gene on the cells was, they performed X-ray fluorescence experiments on thin sections of a specific region of the brain, the substantia nigra, to determine whether the brain cells show accumulation of heavy metals such as iron, copper or manganese. Accumulation of these metals is one of the many symptoms of PD. One of the advantages of using I18 at Diamond for these measurements is that the beamline can perform elemental mapping on the micrometre scale, which is the necessary resolution required for the study of animal cells. They showed a clear accumulation of iron and manganese in the brains of the infected primates.

Dr Tina Geraki, I18’s senior scientist, who has supported the group with their experiments for the past few years, also has a keen interest in the role of metals in health and disease.

To find out more about the I18 beamline please contact the Principal Beamline Scientist Konstantin Ignatyev: konstantin.ignatyev@diamond.ac.uk 

Sikora, J. et al. Nigral ATP13A2 depletion induces Parkinson’s disease-related neurodegeneration in a pilot study in non-human primates. npj Parkinsons Dis. 10, 141 (2024). DOI: 10.1038/s41531-024-00757-4