Mutation in PINK1 Gene Increases Risk for Early Parkinson’s Disease

Researchers at Mayo Clinic’s campus in Florida have found a genetic mutation that may increase the risk for developing Parkinson’s disease earlier than usual.

The study, “Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism,” was published in the journal Brain.

The result of a collaboration of more than 32 researchers in seven countries, this study led to the discovery of a single mutation in the PTEN-induced putative kinase 1 (PINK1) gene as the underlying cause for increased risk to suffer from Parkinson’s disease at early ages.

“We know that if you have mutations in both copies of PINK1, age at onset of Parkinson’s will usually be younger than 45. This study showed that if a person inherited a specific mutation in just one PINK1 gene, the disease could develop at about age 55 or so. By contrast, the most common, nonfamilial forms of Parkinson’s develop at about age 65,” Wolfdieter Springer, PhD, a neuroscientist at the Mayo Clinic and lead author of the study said in a press release.

Now, the international collaboration tackled how a single mutated PINK1 allele results in earlier disease development. PINK1 works in partnership with another gene, PARKIN, to ensure that mitochondria in neurons remain healthy. Energy production is the key responsibility of mitochondria, and defects in these organelles have been shown to underlie several brain disorders, including Parkinson’s.

Upon damage to mitochondria, both PINK1, in concert with PARKIN, ensure proper destruction of these damaged mitochondria. So, PINK1- PARKIN works as a “quality control” system for mitochondria.

“The mitochondria are like a cell’s nuclear power plant that provides fantastic energy when they are running well,” Springer said. “But, when something goes wrong, the result can be catastrophic for the brain cell, causing neurodegeneration.”

Researchers discovered that a specific mutation (p.G411S) in one copy of PINK1 impairs the production of a healthy PINK1 protein, therefore compromising the quality control system and establishing the conditions for neurodegeneration.

“This rare mutation has an outsized effect, and the remaining levels of functional PINK1 protein are not enough to cope with damaged mitochondria,” Springer said.

These results identify a pathway that may be common to other neurodegenerative disorders, and identify a potential target for therapeutic approaches.