PARK 9 Gene: the Rescue Against Manganese-induced Parkinson's Disease

Author:  Suvash Shrestha
Institution:  Kathmandu Medical College, Nepal

Assistant Professor Aaron D. Gitler and colleagues, from the University Of Pennsylvania School Of Medicine, claim to have found a gene which can prevent manganese-induced Parkinson's disease as reported in Nature Genetics. The gene called PARK9, localized in the vacuole membrane of a cell, helps to store manganese and thereby prevent its toxicity, Gitler explained.

Parkinson's disease is a degenerative disease of the brain that often impairs motor skills, speech, and other functions. There is gradual loss of neurons in the substantia nigra, which is a vital part of the human brain and plays important role in the regulation of activities like eye movements, learning, and addiction. The classical symptoms of this disease include tremors, rigidity and bradykinesia. However, there could be non-specific symptoms like tiredness, mental slowness, depression and small handwriting.

Manganese poisoning shows similar symptoms as Parkinson's disease. Since it is a naturally occurring mineral, welders, railroad workers, miners, and steel workers are exposed more to this mineral and have a higher incidence of Parkinson-like symptoms than those who do not work in these occupational environments.

In Parkinson's disease, a protein named alpha-synuclein misfolds and forms a clump, which ultimately kills the host cell. Gitler noticed the same phenomenon in the yeast cells that he was studying. He then started to look for genes which could prevent this phenomenon and was successful in his discovery. "One of the genes that we found was a previously uncharacterised yeast gene called YOR291W. No one knew what it did back in 2006," he recalled.

In the meantime, researchers in Europe published studies about a family that had an early onset form of Parkinson's disease caused by mutations in the PARK9 gene. Gitler was interested to see which of the yeast genes was closest to PARK9 and found it to be YOR291W, which he renamed YPK9 (Yeast PARK9).

After realizing the relationship between PARK9 and alpha-synuclein, Gitler and his team set out to find the function of YPK9. When they deleted the gene from yeast, the cells remained viable and functioned normally. Next, when they exposed the same mutant cells to different metals such as zinc, copper, manganese, and iron, the cells could not survive in the presence of manganese.

"This was astonishing, because it was known for years that welders and miners that inhale manganese get a Parkinson's-like disease called manganese poisoning," said Alessandra Chesi, first co-author of the study.

Gitler later found that the protein made by YPK9 was localized in the vacuole membrane in the yeast cell. Vacuoles are inner cell components that encase toxic substances for later disposal. "Our hypothesis is that the vacuole is sitting there and taking in manganese and sequestering it for detoxification, keeping it away from other cell organelles," explained Gitler, "But, having a mutation in the PARK9 gene causes problems for this process in yeast and possibly in humans."

After putting together all the pieces, the research gave much evidence that PARK9 prevented manganese poisoning, which can induce Parkinson's disease. The role of PARK9 in preventing Parkinson's disease was confirmed and opens a new door as to the connection between both genetic and environmental causes of Parkinson's.

Written by: Suvash Shrestha

Edited by: Brittany Raffa and Renee Gilberti

Published by: Hoi See Tsao