At a Glance
- A mutation in the LRRK2 gene appears to be linked to Parkinson’s disease, making it a key target for drug development; however, its gene product, LRRK2 protein, is difficult to study.
- To determine the structure of LRRK2, researchers need LRRK2 protein crystals that are large and of high quality.
- Crystals grown in microgravity are often larger and more well-ordered than crystals grown on Earth.
- The Michael J. Fox Foundation launched its most recent investigation to crystallize LRRK2 onboard the ISS National Lab on Northrop Grumman CRS-10.
We know that the symptoms of Parkinson’s disease originate from a decrease in dopamine production due to the loss of neurons. But why are the neurons lost? Is there a genetic cause?
According to more than a decade of research, a mutation in a gene known as LRRK2 (leucine-rich repeat kinase 2) appears to be linked to Parkinson’s disease in some patients. However, despite the knowledge that this gene may be involved in some cases of the disease, researchers have been unable to unlock the full potential of this genetic research because of the difficulty in studying its gene product, LRRK2 protein.
The role of LRRK2 in the development of Parkinson’s is well established. Mutations in the LRRK2 gene are associated with increases in LRRK2 protein, which in turn modifies other proteins. Ultimately, the chain of events set off by the genetic mutation can cause neurons to degenerate and symptoms of Parkinson’s to develop.
The Michael J. Fox Foundation, which is dedicated to finding improved therapies and ultimately a cure for Parkinson’s disease, has partnered with the International Space Station (ISS) National Lab to investigate the structure of the LRRK2 protein by crystallizing it in microgravity. For some proteins, crystallization in space produces larger and higher-quality crystals than on Earth.
The Michael J. Fox Foundation partnered with the ISS National Lab in its investigation of LRRK2’s structure.
“Therapies targeting LRRK2 are already advancing, even though we don’t know its atomic structure,” said Marco Baptista, Director of Research Programs at The Michael J. Fox Foundation. “But we can’t yet perform structure-based drug discovery that fully leverages the insight of the drug’s binding pocket. To get an accurate picture of the structure, researchers need LRRK2 protein crystals that are large and have few defects. However, LRRK2 crystals grown on Earth suffer from limitations in these areas.”
Protein crystals grown onboard the ISS National Lab don’t grow like they do on Earth—with less pull from gravity, crystals can grow larger and in a more uniform and ordered pattern. Once the large, well-ordered crystals return to Earth, they are then easier to observe using high-resolution imaging techniques. Thus, crystallization of LRRK2 on the ISS could lead to improved structure determination of LRRK2 and help advance structure-based drug design.
The Michael J. Fox Foundation’s first investigation to crystallize LRRK2 on the ISS National Lab launched on SpaceX commercial resupply services (CRS)-12. Although the resulting crystals were of high quality, they were not large enough to improve structure determination of LRRK2.
Recently, The Michael J. Fox Foundation sent a second investigation to the ISS National Lab to crystallize LRRK2. This investigation launched on Northrop Grumman CRS-10 and is using a different type of hardware to enable larger crystal growth. This time, the team, which also includes researchers from Merck & Co. and Goethe University Frankfurt, is also able to monitor the crystals in orbit and make any necessary adjustments to improve crystal growth.
The LRRK2 crystals from this most recent investigation will return to Earth on SpaceX CRS-16, which is currently scheduled to launch in December and return in January. Once the crystals are back on the ground, they will be imaged and studied. The results from these and other space-grown crystals could help researchers gain new knowledge in the fight against Parkinson’s and other diseases.
Interestingly, the knowledge gained from this and related studies could also be beneficial for those who have Parkinson’s disease but do not have the LRRK2 mutation. Even when mutations in other genes may be at fault, many of the symptoms of Parkinson’s disease are the same. Thus, treatments developed using the knowledge gained from studying LRRK2 could be broadly effective for the one million people in the U.S., and 6 million worldwide, currently living with Parkinson’s disease.