Genes Controlling Molecular Pathway Increase Risk For Parkinson’s Disease, Study Finds

Genes that control a molecular pathway responsible for moving biological cargo into cells contribute to the risk of developing Parkinson’s disease, researchers report.

The study, “The Endocytic Membrane Trafficking Pathway Plays a Major Role in the Risk of Parkinson’s Disease,” was published in Movement Disorders.

The movement of molecules into and out of cells is important for cellular communication. Scientists call the process of movement into cells “the endocytic membrane-trafficking pathway,” and it can be used for nutrient uptake, and directing toxic cargo for degradation.

Most cases of Parkinson’s disease are sporadic, meaning that they occur randomly and do not have a specific environmental or genetic cause. Although hereditary cases of Parkinson’s are rare, there’s evidence that some genes do not cause the disease outright, but increase the risk of developing it.

“Aligned with the genetic discoveries, a big effort has been made to identify how those genes interact within biological pathways to elucidate the cellular and molecular processes that could explain the neurodegenerative mechanism,” the researchers wrote.

Previous studies suggest that dysfunction in the endocytic membrane-trafficking pathway contributes to Parkinson’s disease, and several pathway-related genes (VPS35, DNAJC6, RAB7L1, SH3GL2, GAK, CHMP2B, LRRK2 and PLA2G6) have been proposed to play a part in the process.

Therefore, researchers from the National Institutes of Health (NIH) sought to investigate how 252 endosomal membrane-trafficking-related genes influence the risk of developing Parkinson’s disease.

The investigators used data from genome-wide association studies of the International Parkinson’s Disease Genomics Consortium (IPDGC), which involved 18,869 patients and 22,452 healthy controls, all of European ancestry. A genome-wide association study searches the genome (the complete set of genes present in an organism) for small variations that occur more frequently in people with, for instance, Parkinson’s than in people without the disease. This helps the scientific community identify genes that may increase the risk of developing a particular disease.

The study revealed that 2.14% of the observed genetic variation was related to the endocytic membrane-trafficking pathway, explaining roughly 9.34% of the overall heritability of Parkinson’s disease. Heritability refers to differences in the appearance of a trait across several people that can be explained by differences in their genes. It is not a measure of what causes a trait or, in other words, of “how genetic” or heritable a trait is.

However, scientists only focused on genes that would produce an RNA molecule and later generate a protein. Therefore, their estimates did not include adjacent regulatory genomic regions that may somehow affect the risk of developing Parkinson’s disease.

Taking these regions into consideration, changes in the endocytic membrane-trafficking pathway increased the risk 1.25 times for developing Parkinson’s disease.

For an unbiased analysis of causal effects, researchers then used a technique called Mendelian randomization to pinpoint genes that influenced Parkinson’s disease risk, and identified several endocytic membrane-trafficking pathway genes.

Increased blood expression of VAMP4, ARL8B, and GAK was associated with a reduced Parkinson’s risk, while RABGEF1, VAMP8, CLTCL1, and ITSN1 levels were associated with an increased risk.

Furthermore, increased gene expression of SH3GL2 and GAK within the brain was causally linked to Parkinson’s risk, whereas ARL8B expression was negatively associated.

The addition of a methyl group (a chemical group containing one carbon and three hydrogen atoms) to a DNA molecule modifies gene function and affects gene expression. The process is known as DNA methylation and has been associated with Parkinson’s disease.

Accordingly, researchers reported that higher methylation rates of GAK and HSPA1B were positively associated with Parkinson’s disease risk, whereas PLEKHM1 and VPS39 were negatively correlated with disease risk.

Of the 252 analyzed genes, 151 were found to be expressed in dopamine-releasing neurons in adult mouse brains.

The NIH team stated that its methodology could be used to study other important molecular pathways in Parkinson’s, and provide additional understanding about disease-related genetic risk factors.

“Unravelling the genetics underlying (Parkinson’s disease) will provide therapeutic options for drug discovery and ultimately could lead to the development of effective interventions,” the researchers said.