Lysosome Impairment Can Cause Excess Iron Found in Brains of Those with Parkinson’s Disease; Normally Sequestered Iron Escapes into Body of Neuron Where It Causes Toxic Oxidative Stress Leading to Neuronal Cell Death
Wed, 01/27/2016 - 17:37 — bioquicknews

It's long been known that excess iron is found in the brains of patients with Parkinson's disease, an incurable neurodegenerative condition that affects motor function. The mechanism by which the iron wreaks damage on neurons involved in Parkinson's
disease has not been clear. Now, new research from the laboratory of Julie K. Andersen, Ph.D, at the Buck Institute for Research on Aging in Novato, California just north of San Francisco, suggests that the damage stems from an impairment in the lysosome,
the organelle that acts as a cellular recycling center for damaged proteins. Dr. Andersen and collaborators report that the lysosome impairment allows excess iron to escape into the neurons where it causes toxic oxidative stress. The research was
published online in The Journal of Neuroscience on January 27, 2016. The article is titled “Regulation of ATP13A2 via PHD2-HIF1 Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease.” Lysosomes are key to a
process called autophagy, whereby damaged proteins are broken down into building blocks that are used to make newly-built proteins to take their place. It's the cellular equivalent of recycling. With age, the ability of the lysosome to participate in
autophagy becomes slower, resulting in the build-up of non-protein "garbage" within the cells. Less-than-optimal autophagy has been associated with several age-related diseases, including Parkinson’s disease. "It's recently been realized that one of
the most important functions of the lysosome is to store iron in a place in the cell where it is not accessible to participate in toxic oxidative stress-producing reactions," said Dr. Andersen, Senior Scientist and faculty member at the Buck Institute. "
Now we have demonstrated that a mutation in a lysosomal gene results in the toxic release of iron into the cell resulting in neuronal cell death."

Spearheaded by staff scientist Shankar J. Chinta, Ph.D., the work (done in both mice and cultured human dopaminergic cells) involved a mutation in a gene (ATP13A2) associated with a rare early-onset form of Parkinson's disease called Kufor-Rakeb syndrome.
When researchers knocked out ATP13A2, the lysosome was unable to maintain the balance of iron within the cell.

The mutation responsible for Kufor-Rakeb was identified in 2010. Those suffering from this condition, which is named for the village in Jordan where the syndrome was first described, experience disease onset in adolescence.

"Mutations in this same gene have also been recently linked to sporadic forms of Parkinson's disease," said Dr. Andersen. "This suggests that age-related impairments in lysosomal function that impact the ability of neurons to maintain a healthy balance
of iron are part of what underlies the presentation of Parkinson's disease in the general population."

Dr. Andersen has a long-standing interest in the role of excess iron in Parkinson's disease and this current work provides an example of the value of basic research in drug discovery.

In 2003, Dr. Andersen’s lab showed that tying up excess iron with a metal chelator protected mice from the ravaging effects of the well-known Parkinson's inducing toxin, MPTP.

The study provided an important link between the observed excessive iron in the brains of Parkinson's disease patients and oxidative stress associated with neurodegeneration.

"The issue with iron chelation is that it's a sledge hammer -- it pulls iron from the cells indiscriminately and iron is needed throughout the body for many biological functions," said Dr. Andersen.

"Now we have a more specific target that we can hit with a smaller hammer, which could allow us to selectively impact iron toxicity within the affected neurons."

Other Buck Institute scientists involved in the study include Subramanian Rajagopalan and Anand Rane.

BUCK INSTITUTE FOR RESEARCH ON AGING

The Buck Institute is the U.S.'s first independent research organization devoted to geroscience -- focused on the connection between normal aging and chronic disease. The Buck Institute is dedicated to extending “Healthspan,” the healthy years of
human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases.

Buck scientists strive to discover new ways of detecting, preventing, and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes, and stroke. In their collaborative
research, Buck scientists are supported by the most recent developments in genomics, proteomics, bioinformatics, and stem cell technologies. For more information, see http://www.thebuck.org.

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