When mutated, ATP10B is no longer able to provide instructions to make a functional protein that is necessary to transport a fatty substance — known to play a key role in Parkinson’s — out of lysosomes, the cell compartments responsible for digesting and recycling different types of molecules.
The study, “Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export,” was published in the journal Acta Neuropathologica.
Parkinson’s disease is a neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons in the substantia nigra — a region of the brain responsible for movement control — along with brain inflammation.
In about 5%–15% of Parkinson’s patients, genetic mutations in certain genes are responsible for the inheritance of the disease from one generation to the next. These mutations associated with familial forms of Parkinson’s are highly penetrant, meaning that once passed down, they are very likely to trigger the onset of the disease at some point during the carrier’s lifetime.
However, the contribution of genetic factors to the development of Parkinson’s in patients with non-familial forms of the disease is less clear. In these individuals that have a so-called sporadic form of Parkinson’s, scientists believe the onset of the disease is dictated by a combination of genetic and environmental factors.
In the study, researchers have now discovered that mutations in the ATP10B gene increase the risk a person has of developing Parkinson’s disease.
The team screened the DNA of 52 patients with early-onset Parkinson’s who had all developed the disease under the age of 50 (23.1% had a family history of the disease). However, these patients did not carry known disease-causing Parkinson’s mutations, which allowed the team to search for novel Parkinson’s genes.
After performing whole-exome sequencing — a technique that allows researchers to analyze the DNA sequence of all genes that encode proteins (exome) — they found that three individuals in the group carried two mutations in ATP10B, one in each copy of the gene that had been inherited from each of the parents.
The researchers also screened a group of 617 unrelated Belgian patients with Parkinson’s (mean age of 60 years at disease onset; 18.6% with a positive family history) and 226 with dementia with Lewy bodies (DLB) (mean age of 70.8 years at disease onset; 23.0% with a positive family history). Additionally, a group of 598 unrelated healthy individuals served as controls.
Mutations in ATP10B were found in six patients with Parkinson’s, one patient with DLB, and two individuals from the control group.
Although the higher number of mutant carriers among those with Parkinson’s suggested an enrichment of these mutations in this group, investigators found no statistically significant differences when compared to controls, most likely due to the small number of study participants. They also noticed there was a high variability among patient carriers in the age at which they started experiencing their first symptoms.
Among the patient carriers, the age at disease onset varied from 24 to 68 years. The high variability in age at disease onset and the presence of mutant carriers in the control group are probable due to variable effects of single mutant alleles (different forms of the same gene) on ATP10B expression or activity, the researchers wrote.
Importantly, the team found that ATP10B encodes a protein transporter for glucosylceramide, a fatty substance that plays a key role in Parkinson’s.
Under normal circumstances, the protein transporter carries glucosylceramide out of lysosomes. However, when ATP10B is mutated, the protein is no longer able to perform its normal function.
The scientists believe the dysfunction of the protein transporter in combination with the reduced activity of the ATP10B gene disturbs lysosomal function, promotes neuronal loss, and increases neurons’ sensitivity to certain environmental risk factors, thereby contributing to the development of Parkinson’s.
“In conclusion, we identified ATP10B as a [Parkinson’s disease] risk gene and functionally characterized ATP10B as a [transporter] that regulates lysosomal functionality and provides neuroprotection,” the researchers wrote.
The team is currently working on possible therapeutic strategies aimed at controlling the activity of the ATP10B gene in the context of Parkinson’s disease.
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