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Breakdown in Recycling System Leads to Cell Death in Parkinsonís
- Jul 15 2013
Scientists funded in part by the Parkinson’s Disease Foundation (PDF) have discovered one reason why mutations in the gene LRRK2 may lead to some cases of Parkinson’s disease. It is that they may interfere with the normal process by which recycling takes place in cells. The discovery, which was reported in the March 3 online issue of Nature Neuroscience, provides insights into how the cell’s recycling system plays a role in PD overall, and points to potential strategies for treatments.
Normal cells, including those in the brain, use a recycling and waste disposal system to stay healthy. The process – known as chaperone-mediated autophagy – begins when molecules called chaperones patrol for damaged proteins and then transport them to a recycling center (the lysosome). After arriving there, the damaged proteins travel to the interior region of the lysosome, where they are broken down into components that can be reused.
Researchers led by Ana Maria Cuervo, M.D., Ph.D., at Albert Einstein College of Medicine in New York City, and David Sulzer, Ph.D., at PDF’s Research Center at Columbia University Medical Center, also in New York, were the first to identify (in 2004) the importance of this cellular recycling process to PD. Building on that earlier work, they began to look at the LRRK2 protein and its role in the recycling process. (It was already known that mutations in the LRRK2 gene are among the most commonly-found known genetic factors in PD.)
To understand what happens to both normal and faulty LRRK2 proteins during this recycling process, the team studied neurons from several different sources – lab-grown neurons from mice, lab grown neurons made from the skin of people with PD using stem cell technology, and neurons from brain tissue donated from people who had LRRK2 mutations.
- Chaperone-mediated autophagy – the regular recycling process – was capable of recycling healthy LRRK2 protein, but it was not as successful in breaking down those LRRK2 proteins that had the mutation found in people with PD.
- Faulty LRRK2 proteins became stuck to the exterior of the lysosome. Like a lid stuck on a trash can, these faulty LRRK2 proteins then prevented other proteins, such as alpha-synuclein, from getting broken down and recycled.
What Does It Mean?
Although the vast majority of cases of PD have no known genetic cause, among those that do run in families the most common mutations occur in the LRRK2 gene. The importance of this work by Drs. Cuervo and Sulzer is that it suggests, for the first time, why the faulty LRRK2 protein is harmful, and how it can block the normal cellular recycling process.
Their discovery is part of a growing body of literature that shows how important cellular recycling can be to the health of a cell. In much the same way that a sanitation strike can hit a city and cause waste to accumulate, the same thing can happen to a cell, jeopardizing its health. Brain cells may try to compensate by creating waste dumps, but eventually toxic stress will kill the cells.
The studies of Dr. Cuervo and Dr. Sulzer over the years have spotlighted the need for developing therapies that can help restart or speed up cellular recycling – therapies that could potentially benefit people whose PD has no known genetic cause as well as those who have LRRK2 mutations.
As part of its $5 million in research funding each year, PDF supports the work of three Research Centers, one of which is at Columbia University. This study illustrates the importance of funding scientists through a center model that allows them the flexibility and long-term support to collaborate on basic, translational and clinical research.
It is also noteworthy that this study used post-mortem brain tissue from people who lived with Parkinson's disease, derived from the PDF-supported brain bank at Columbia. This type of donation, the greatest gift, is vital to advancing PD research.
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Reference: Orenstein SJ, Kuo S-H, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (2013) Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci 16:394–406. DOI: 10.1038/nn.3350 http://dx.doi.org/10.1038/nn.3350.
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Source Date: Jul 15 2013