Substantia nigra of the midbrain and its dopaminergic neurons, 3D illustration
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A potential landmark genetic association study for the neurodegenerative disorder Parkinson’s has uncovered a new risk variant. The team, which included scientists from the University Medical Center Utrecht, Indiana University School of Medicine, and UMass Chan Medical School, combined whole genome and exome sequencing data from 2184 familial Parkinson’s disease patients, resulting in the discovery of a specific mutation in a gene that encodes a small GTPase known as RAB32. In the Nature Genetics article, the researchers show that the toxicity of this variant is most probably mediated through the enhancement of activity for LRRK2, a known Parkinson’s disease target.

Discovering familial Parkinson’s genes

“Familial cases” make up about 10–15% of Parkinson’s disease patients; this label is traditionally reserved for those who are known to have at least one first-degree relative with the disease. Finding causal rare variants in familial Parkinson’s disease has greatly advanced our knowledge of the disease. This has led to the development of new drug targets, biomarkers, and important insights into the mechanisms of the disease. Seven genes are currently confirmed to be associated with familial Parkinson’s disease.

These familial Parkinson’s disease genes were discovered using various family-based study designs, such as linkage analysis, homozygosity mapping, and segregation filtering. However, traditional family-based research methods often fail to detect causal variants because of factors such as genetic diversity within families, low penetrance, and small sample sizes within families.

RAB32 is a Parkinson’s disease risk variant

The study was led by Dongbing Lai, PhD, and graduate student Paul J. Hop, who combined sequencing data from 16 cohorts, including whole-exome and whole-genome sequencing (WGS) data, totaling 2,824 individuals with familial Parkinson’s disease and 78,683 controls. Notably, they retained individuals of predominantly European ancestry who met quality control criteria (2,756 cases and 73,879 controls), followed by unrelated individuals, yielding an association cohort of 2,184 index familial Parkinson’s disease cases (one affected individual per family) and 69,775 controls.

Exome-wide single-variant analyses identified four significant LRRK2, GBA, and RAB32 variants. Among them, three had been previously implicated in Parkinson’s disease, including one in GBA and two in LRRK2. A new variant, c.213C > G/p.S71R, was discovered in RAB32. This variant converts a serine to an arginine. This high-risk variant is found in approximately 0.7% of familial Parkinson’s disease cases but only in 0.004% of controls.

The 70-member RAB family of small GTPases is involved in controlling intracellular vesicular transport, and several RAB family members have been identified as either substrates or regulators of LRRK2. Compared to wild-type, RAB32 expression in HEK293 cells considerably enhanced LRRK2 phosphorylation and coimmunoprecipitation. Previous phosphoproteomic studies showed that Ser71 is the only known phosphorylation site on the RAB32 protein. This means that the S71R variant probably interferes with this phosphorylation event, which the study’s authors postulate is how the S71R variant alone increases the likelihood of developing Parkinson’s disease.

These results are in line with a model where the S71R variant selectively changes RAB32’s function, elevating LRRK2 interaction and activity. These results provide new insight into the molecular connections between RAB family biology, LRRK2, and the risk of Parkinson’s disease by linking mutant RAB32 to a critical pathogenic mechanism in the disease—the activity of the LRRK2 kinase.

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