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.

Cuervo’s team and collaborators made their findings by examining brain tissue and skin cell lines from Parkinson’s patients transformed into neurons in the laboratory, as well as by studying mice bred to have the normal and mutated forms of the gene.

The function of the healthy LRRK2 protein in the brain remains unclear, but it seems to be involved in the transmission of signals from one nerve cell to another, Cuervo added.

In Parkinson’s: Mutations in the LRRK2 gene produce impaired proteins that block portals to the cell’s garbage recycling station or lysosome. When these portals are blocked, large amounts of the protein alpha-synuclein pile up, clumping into brain-damaging Lewy bodies.
Courtesy of Ana Maria Cuervo
In Parkinson’s: Mutations in the LRRK2 gene produce impaired proteins that block portals to the cell’s garbage recycling station or lysosome. When these portals are blocked, large amounts of the protein alpha-synuclein pile up, clumping into brain-damaging Lewy bodies.

Two previous studies, published in 2008 and 2009, also established a link between Parkinson’s and malfunctions of the cell’s waste disposal systems. Those studies examined a gene called GBA and mutations in it most common among Ashkenazi Jews. GBA is associated with Gaucher’s disease, a rare genetic disorder that only develops when a person inherits two copies of a mutated gene. But scientists began to wonder: Could healthy people with a GBA mutation be at greater risk for Parkinson’s?

“The story of GBA is fascinating,” said Israeli geneticist Avi Orr-Urtreger, who worked on both studies. “It was a surprise that people tried to connect carriers for a Gaucher mutation — who are, after all, healthy people — with Parkinson’s. For a long time the scientific community didn’t believe there was a link between GBA and Parkinson’s putting these people at higher risk until we published our paper.”

Gaucher’s, as scientists have known for some time, is also a disease that involves a malfunctioning of the lysosomes. In this case the cell’s recycling plants fail to properly break down certain fats. The two studies on GBA “started to convince people to look deeper into the lysosomes” to understand Parkinson’s, said Orr-Urtreger, director of the Genetic Institute at Tel Aviv Sourasky Medical Center and an associate professor of pediatrics and human genetics at the Sackler Faculty of Medicine at Tel Aviv University.

In April, Orr-Urtreger published a study in the journal Neurology demonstrating that carriers for yet another, significantly rarer, lysosomal disorder were at higher risk of developing Parkinson’s. This mutation, SMPD1 p.L302P, found among Ashkenazi Jews, results in Niemann-Pick A, a devastating childhood disorder when inherited from both parents. But as Orr-Urtreger found, it is also associated with higher rates of Parkinson’s among healthy carriers.

“Lysosomes are currently very promising in the world of Parkinson’s research,” noted Roy Alcalay, assistant professor of neurology at the Columbia University Medical Center — which also collaborated on the March Nature Neuroscience study — although he cautions that “Parkinson’s is probably more than one disease and people probably get it for different reasons.”

Indeed, having a mutation on a LRRK2 or GBA gene does not mean that a person is destined to develop Parkinson’s. Estimates that a person with the G2019S mutations on LRRK2 will develop Parkinson’s vary widely from as low as 30% to as high as 80%. And while approximately one third of Parkinson’s among Ashkenazi Jews has been associated with either LRRK2 or GBA, two thirds have not been linked to any gene.

Researchers agree that Parkinson’s also has environmental triggers. Vietnam vets who were exposed to Agent Orange, for example, have been found to develop Parkinson’s at a much higher rate than the general population. And it is likely that a person who develops Parkinson’s does so as a result of not one, but several factors. “You need several hits,” said Orr-Urtreger. These can be several genes acting together or various environmental factors or a mix of both. Age alone is a risk factor for the disease.

“Right now drugs are just treating the symptoms of the disease. With LRRK2 we are trying to figure out how we can develop a molecule that will prevent the protein from getting stuck,” said Cuervo. But her reach is greater. “Rather than going one disease at a time, we are looking at keeping this cleaning system going, in general. We have drugs that are promising.”

“I’m optimistic,” added Alcalay. “I think the genes that were discovered give us clues to what causes Parkinson’s and give us a way to manipulate the pathways to slow down Parkinson’s or prevent it. It is also possible that if you discover something that slows down Parkinson’s with these mutations it can also be helpful for the entire Parkinson’s population.”

Talia Bloch writes on culture, religion and science and contributes regularly for the Forward.


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