August 24, 2015

Study Details Process Involved in Parkinson’s Disease

At a Glance

  • Researchers detailed how cells dispose of damaged mitochondria, a process that can lead to neurodegenerative and other diseases when gone awry.
  • The results suggest a new pathway to target to treat disorders linked to faulty mitochondrial disposal, including some forms of Parkinson’s disease and ALS.
Mitochondria Mitochondria appear as green speckles around the blue nuclei of the cells used in this study.Nature

Roughly 50,000 Americans are diagnosed with Parkinson’s disease each year. The disease is caused by the death of neurons in the brain that control movement. Although most cases of Parkinson’s don’t have a clear cause, researchers have linked some cases to the genes that code for the proteins parkin and PINK1.

Parkin and PINK1 work together in cells to remove energy-producing structures known as mitochondria when they become damaged. Studies have shown that mutations affecting PINK1 or parkin derail this process, which is called mitophagy. When neurons can’t perform mitophagy, they eventually die. Recent studies have linked defects in mitophagy to some forms of Parkinson’s disease as well as other diseases, including amyotrophic lateral sclerosis (ALS).

Damaged organelles are tagged for destruction with chains of a small protein called ubiquitin. In mitophagy, PINK1 and parkin cooperate to attach ubiquitin chains to damaged mitochondria. PINK1 accumulates on the surface of damaged mitochondria and marks both ubiquitin and parkin with chemical tags called phosphate groups that activate parkin activity. Parkin builds chains of ubiquitin on the mitochondrial surface. A team of scientists led by Dr. Richard Youle of NIH’s National Institute of Neurological Disorders and Stroke (NINDS) have been investigating how this process works. Their latest findings were published on August 20, 2015, in Nature.

The team created cells that lacked parkin and 5 proteins called autophagy receptors, which bind to ubiquitinated cargo to help cells get rid of damaged materials. These cells couldn’t dispose of damaged mitochondria. When the researchers restored the function of the autophagy receptors optineurin or NDP52, the cells regained that ability. Restoring other autophagy receptors had little or no effect. This suggests that optineurin and NDP52 play crucial roles in mitophagy.

Further experiments showed that PINK1 recruits optineurin and NDP52 by phosphorylating ubiquitin. While cells containing either optineurin or NDP52 could perform mitophagy without parkin, parkin dramatically increased the process. Cells could not perform mitophagy at all without PINK1.

Parkin used to be considered crucial to mitophagy, but these findings imply that PINK1 is actually the critical driver of this system. Parkin plays an amplifier role by attaching more ubiquitin to damaged mitochondria for PINK1 to phosphorylate.

“A number of companies are trying to develop drugs to activate this pathway,” Youle says. “Some of them are trying to find drugs that activate parkin, but this new model might suggest a different strategy. It may not be so important to activate parkin; it may be more important to activate PINK1.”

These experiments were only performed in isolated cells, so whether this process works the same way within the body remains to be confirmed. Future studies will also need to examine how phosphorylated ubiquitin interacts with optineurin, NDP52, and other proteins to promote mitophagy.

Related Links

Reference:  The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ. Nature. 2015 Aug 20;524(7565):309-14. doi: 10.1038/nature14893. Epub 2015 Aug 12. PMID: 26266977.

Funding: NIH’s National Institute of Neurological Disorders and Stroke (NINDS).