How 2 Proteins Affect Pathway Linked to Early Onset Disease Detailed for Possibly 1st Time

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

Share this article:

Share article via email
gene therapy trial results

The significance — physiological and clinical — in the interaction of two proteins known to be associated with early onset Parkinson’s disease, PARKIN and PINK1, is detailed, possibly for a first time, by researchers.

Their study, “Phosphorylation of Parkin at serine 65 is essential for its activation in vivo,” was published in the journal Open Biology.

Mutations in the genes coding for proteins two proteins, PINK1 and PARKIN, are associated with early onset Parkinson’s disease — mutations in the Parkin gene account for about 40 percent of Parkinson’s cases in people below age 45.

PINK1 and PARKIN are thought to play essential roles in protecting the brain against stress.

Researchers at the University of Dundee, in the U.K., previously reported that PINK1 is able to detect damages to the cell’s mitochondria — small cellular organelles that provide energy and are known as the cell’s “powerhouses” — and prevent further damage by activating the PARKIN protein.

This occurs via a PINK1-mediated addition of a chemical switch, called a phosphate group, to an amino acid (the building blocks of proteins) in the PARKIN’s protein sequence called serine 65.

Want to learn more about the latest research in Parkinson’s Disease? Ask your questions in our research forum.

Knowledge of the role of PINK1 and PARKIN play in the brain comes mostly from in vitro laboratory studies, while the in vivo (in a live organism) significance of PINK1-mediated phosphorylation (the adding of a phosphate group) of PARKIN serine 65 remained unknown.

Now, an international team led by these researchers developed a mouse model with an altered serine 65 in the Parkin gene, a change that removed this “molecular switch” and prevented PINK1 from activating the PARKIN protein.

Using this mouse model, researchers showed that not only is serine 65 critical for PARKIN’s activation, but it is also necessary for a “protein degradation marker” (i.e., phosphor-ubiquitin) to accumulate in brain nerve cells.

The loss of serine 65 in the PARKIN protein also resulted in impaired motor and balance in the animals, poorly coordinated limbs and mild cognitive defects shown by the animals’ performance on the beam walk test.

In this test, animals are trained to traverse a narrow beam suspended between a starting platform and their home cage. Researchers record the time necessary to fulfill the task and the number of foot slips.

Given the key mitochondrial functions ascribed to the PINK1–Parkin interaction, researchers investigated if the motor problems observed could be attributed to mitochondrial dysfunction.

They found the mice had impaired mitochondrial integrity in a specific brain region involved in movement control, called the striatum, suggesting that PARKIN serine 65 phosphorylation contributes to mitochondrial integrity there.

Importantly, researchers also reported the first clinical and genetic evidence linking Parkinson’s disease  with mutations at PARKIN serine 65 in two patients.

The first case was a 71-year-old Finnish male, who was diagnosed with early onset Parkinson’s at  age 40 and had no reported family history of the disease.

The second case, a 60 year-old Caucasian woman in the U.S. diagnosed at age 54, was identified from the Parkinson’s Progression Markers Initiative (PPMI) —  an ongoing observational study, coordinated by the Michael J. Fox Foundation, of more than 1,300 volunteer participants both with and without Parkinson’s. Its goal is to validate biomarkers and, over time, identify disease risk factors.

Similar to what occurs in the mouse model, these patients’ PINK1 protein lacks the ability to activate the PARKIN enzyme. “Inactivation of this PINK1 phosphorylation site on Parkin alone is sufficient for humans to develop early onset Parkinson’s disease,” the researchers wrote.

“It was particularly gratifying to see that findings from discovery-based science can have such unexpected relevance in Parkinson’s patients,” Tom McWilliams, the study’s first author, said in a press release.

The study concludes:  “We present the most compelling evidence to date demonstrating the physiological and clinical significance of PINK1-dependent Parkin Ser65 phosphorylation. Furthermore … our research indicates that inactivation of this PINK1 phosphorylation site on Parkin alone is sufficient for humans to develop early onset Parkinson’s disease (PD).”

Researchers now hope to determine how the interplay between PINK1 and PARKIN may affect other pathways in living models of the disease.

Your Parkinson’s Community

Woman laying down illustration

Visit the Parkinson’s News Today forums to connect with others in the Parkinson’s community.

View Forums