A Common Mutation Behind Parkinson's Disease May Have Other Side-Effects

A Mutation of the LRRK2 Gene Prevents Protein Recycling

Seeking A Cause: Professor Ana Maria Cuervo (right)  with investigator Samantha J. Orenstein work at a cellular level to understand Parkinson’s.
Courtesy of Ana Maria Cuervo
Seeking A Cause: Professor Ana Maria Cuervo (right) with investigator Samantha J. Orenstein work at a cellular level to understand Parkinson’s.

By Talia Bloch

Published August 06, 2013, issue of August 16, 2013.
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Recycling for the health of our planet is well understood. But recycling to keep our bodies going? Scientists are finding that the recycling that takes place within the body’s trillions of cells every day plays a key role in aging and disease. It is also at the center of recent findings regarding Parkinson’s Disease and the genes that have been linked to it in Ashkenazi Jews.

A study published in March in Nature Neuroscience reported that mutations on the LRRK2 gene, which is responsible for approximately 15% of Parkinson’s among Ashkenazi Jews, leads to the malfunctioning of a disposal system in the cell that recycles old proteins and breaks them down into their component parts for reuse.

“In all the cells in your body there are systems for eliminating damaged proteins. This cleaning happens daily and it is important that it do so,” said lead author Ana Maria Cuervo of the Albert Einstein College of Medicine in the Bronx. “What we found is that the LRRK2 protein just happens to be blocking the cleaning system.”

Patients with Parkinson’s, a neurodegenerative disease marked by tremors, slowed movement, gait disruptions and balancing difficulties, all have a buildup of abnormal clumps of proteins, or Lewy bodies, in their brain cells. The main constituent is a protein called alpha-synuclein.

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For many years, Parkinson’s was not thought to have a genetic basis. But over the past 15 years, researchers have identified a host of genes associated with it. The most common is the LRRK2 gene, identified in 2004. Two years later, one of the mutations on LRRK2, called G2019S, was identified as a risk factor for Parkinson’s in Ashkenazi Jews. Still, the link between mutations on LRRK2, which give rise to abnormal LRRK2 proteins, and the buildup of alpha-synuclein remained a mystery.

Now Cuervo, professor of developmental and molecular biology, chair for the study of neurodegenerative diseases and co-director of the Institute for Aging Research at Einstein, thinks she may have found some answers.

“The cellular cleaning system in all of us declines with age,” said Cuervo. This recycling system, or autophagy, occurs in cellular structures called lysosomes that can be pictured like tiny vacuums with many ports of entry through which proteins are sucked up and broken down, she explained. The ports vary in nature and a protein’s properties will determine which port it can pass through. As we age, more and more of the ports lose function and become disabled so that each lysosome has fewer and fewer ports available for proteins and other debris to pass through — and more waste accumulates inside the cell.

“The normal LRRK2 protein passes easily into the vacuum,” said Cuervo, “But the mutation changes the shape of LRRK2 enough so that it gets stuck and covers the mouth of the vacuum, blocking entry to other proteins, most specifically alpha-synuclein.” This is how a mutation in LRRK2 leads to a buildup of alpha-synuclein.


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