Journal News

JBC: Researchers link
new protein to Parkinson’s

Laurel Oldach
Oct. 1, 2019

Researchers in Japan are reporting new insight into how the Parkinson’s disease-associated protein parkin selects its targets. The finding might improve experimental therapies for Parkinson’s that aim to boost parkin activity.

This image of cells with damaged mitochondria shows overlap
Koyano et al./JBC 2019
This image of cells with damaged mitochondria shows overlap, in yellow, between parkin protein in green and the mitochondria, shown in red.

Cells depend on parkin to help get rid of damaged mitochondria. The research, published in the Journal of Biological Chemistry, suggests that parkin depends on other proteins, including one called MITOL that has not been linked previously to Parkinson’s disease, to direct it to those damaged mitochondria.

Parkin adds a degradation tag called ubiquitin to proteins on the mitochondrial surface. In some patients with familial Parkinson’s disease, parkin activity is disrupted and bad mitochondria cannot be destroyed. Harmful byproducts from those bad mitochondria can damage neurons. By understanding how parkin works and what goes wrong when it’s mutated, researchers hope also to help patients with other forms of Parkinson’s disease.

While other ubiquitin-tagging proteins, known as E3 ligases, recognize specific amino acid sequences on their substrates, parkin has many known substrates that don’t seem to share a sequence in common. While studying how parkin chooses its substrates, researchers led by Fumika Koyano in Noriyuki Matsuda’s lab at the Tokyo Metropolitan Institute of Medical Science discovered that parkin can tag any lysine-containing protein with ubiquitin — even a bacterial protein not ordinarily found in the cell — as long as it’s present at the surface of the mitochondria.

“Parkin is not regulated by its substrate specificity,” Koyano said of the finding. Instead, control of parkin activity comes from how it is recruited and activated by other proteins.

The discovery that activated parkin is not terribly selective led Koyano and her colleagues to take a closer look at parkin’s recruitment and activation. Some details of that process are well known; for example, a protein called PINK1 is known to boost parkin activity. But Koyano and colleagues discovered a new step that must happen before PINK1 can contribute to parkin activation. They found that parkin acts more rapidly when a first ubiquitin molecule is already present, acting as a seed for the addition of more ubiquitins. In most cases, the researchers found, this seed ubiquitin is added by a protein called MITOL, which had not been linked previously to Parkinson’s.

The research could contribute to the design of new drugs, some of which aim to boost parkin activity to slow the advance of Parkinson’s disease.

“If we achieve upregulation of seed ubiquitylation on mitochondria,” Koyano said, “it might accelerate parkin recruitment and parkin activation to eliminate damaged mitochondria more efficiently.”

Laurel Oldach

Laurel Oldach is a science writer for the ASBMB.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

A molecular determinant of membrane protein targeting
Lipid News

A molecular determinant of membrane protein targeting

Sept. 22, 2021

A study found that a nuclear envelope-localized protein depends on cardiolipin for translocation to its target membrane.

Nautilus founder unspirals a new approach to proteomics
Feature

Nautilus founder unspirals a new approach to proteomics

Sept. 21, 2021

Parag Mallick may be trying to launch a competing proteomics technique, but you won’t catch him badmouthing mass spectrometers.

From pigeon guano to the brain
Health Observance

From pigeon guano to the brain

Sept. 20, 2021

Exploring the journey of the deadly fungal pathogen Cryptococcus neoformans (and its less widespread but still quite serious cousin C. gattii).

Deadly fungal infections
Science Communication

Deadly fungal infections

Sept. 19, 2021

For hospitalized COVID-19 patients, antimicrobial-resistant infections may be a particularly devastating risk of hospitalization.

Scientists must speak out against 'immune-boosting' supplements
Science Communication

Scientists must speak out against 'immune-boosting' supplements

Sept. 18, 2021

Supplements that claim to supercharge your T-cells, make your antibodies hum and otherwise make you invincible are all bunk, and scientists should speak out more about this misinformation.

Finding the right research path
Interview

Finding the right research path

Sept. 16, 2021

Karen Bornfeldt, an associate editor for the Journal of Lipid Research, investigates how diabetes increases cardiovascular disease risk.