In recent years, the Parkinson's disease (PD) research community has dedicated substantial efforts to identify novel genetic factors associated with the pathogenesis of this complex disease. Notably, a significant proportion of these newly discovered genes have emerged as key players in the endolysosomal pathway, shedding light on the central role this cellular process plays in the development and progression of PD.

In 2020, researchers from our laboratory, in collaboration with other groups, conducted a comprehensive study on a cohort of 613 people with PD in Belgium. This study led to the identification of new loss-of-function mutations in a lysosomal gene known as ATP10B, which has emerged as a novel genetic risk factor in PD (source: https://pubmed.ncbi.nlm.nih.gov/32172343/). Notably, six individuals with PD and one individual with dementia with Lewy bodies (DLB) were found to be carriers of compound heterozygous mutations in the ATP10B gene. Furthermore, it's worth noting that three of the people with PD with these ATP10B mutations were diagnosed under the age of 50, highlighting the potential significance of this genetic alteration in early-onset forms of the disease.

ATP10B is a transmembrane lipid flippase located in late endosomes and lysosomes, responsible for coupling lipid export of glucosylceramide (GC) and phosphatidylcholine (PC) to ATP hydrolysis. Experiments have shown that decreased levels of ATP10B in mammalian cell lines result in impaired lysosomal membrane integrity and decreased degradative capacity of these organelles, potentially impacting overall cellular functionality. Given the presence of ATP10B loss-of-function mutations in PD patients, the question arises: What is the impact of ATP10B loss of function on the nigrostriatal dopaminergic system affected in PD?

To answer this question, we conducted experiments using rats as our animal model. Rats were chosen because they possess the ATP10B gene in their genome, and their brains, like humans, contain the nigrostriatal pathway, encompassing both the substantia nigra pars compacta (SNpc) and the striatum. We reduced ATP10B protein levels in the neurons of the SNpc in rats through stereotactic injections of viral vector-mediated shRNA that targeted ATP10B mRNA.

Over the course of a year, we conducted a series of diverse behavioral tests on these rats to assess various aspects of their motor behavior, with the aim of drawing similarities to those observed in PD patients. Intriguingly, we observed that rats with reduced ATP10B levels in the SNpc neurons exhibited impaired motor coordination and balance, were slower, had decreased spontaneous mobility, and increased muscular rigidity. Additionally, when performing Positron Emission Tomography (PET) imaging at different time points, we noted a progressive decrease in the dopamine transporter (DAT) present in dopaminergic terminals in the striatum of these ATP10B knock-down (KD) rats.

This in vivo findings could be explained by examining the pathology of the brains of these rats. We found that ATP10B KD rats had experienced loss of dopaminergic neurons in the SNpc and a reduction in dopaminergic terminals in the striatum, mirroring the same pathological changes observed in the brains of PD patients.

Returning to our initial question, the study allowed us to conclude that decreased levels of ATP10B in the SNpc has a substantial impact on the viability and function of dopaminergic neurons. However, to fully comprehend the role of this protein in PD and the mechanisms underlying dopaminergic neuron death, further research is essential, focusing on the specific molecular pathways affected by ATP10B loss of function.

Understanding the molecular mechanisms that genetic risk factors in PD, such as ATP10B, contribute to, will help us gain a deeper insight into the initial stages of this disease's pathology. This information is essential for the development of therapeutic approaches aimed at not only slowing the progression but also modifying it.

María Sanchiz Calvo, PhD Student in Research Group for Neurobiology and Gene Therapy at KU Leuven, Belgium. She was a speaker at the WPC 2023 in Barcelona.

Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®