The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.
Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.
Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.
The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).
Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.
“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”
Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].