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Unraveling the Connection Between Excess Iron and Parkinson’s

A new study may answer a question that has long puzzled scientists: why does a rare gene mutation cause Parkinson’s disease (PD)? In a report published in the January 27 online edition of The Journal of Neuroscience, researchers implicate a part of brain cells called the lysosome in the toxic build-up of iron. Their findings point to potential new therapy options as well.

Lysosomes are one of the cell’s recycling plants — they break down damaged proteins into pieces that can be reused. They also store extra iron, and slowly release it over time to help cells function. But when a cell becomes stressed, the extra iron may leak too quickly, making the cell even weaker, sometimes killing it.

In earlier research, Julie K. Andersen, Ph.D., and colleagues at the Buck Institute for Research on Aging in Novato, CA, found clues as to how iron stays in balance in neurons. They implicated one gene (called ATP13A2) and one enzyme (called PHD). In this new study, they looked more closely at this gene, ATP13A2, which actually causes a rare, very early onset form of PD in children. To find the connections between the gene, the enzyme, and iron buildup in PD, the researchers studied mice without the ATP13A2 gene and cells (human dopamineneurons) without the ATP13A2 gene.

Results

  • In both mice and human dopamine neurons without the ATP13A2 gene, the lysosomes of the cells were unable to store extra iron properly. In turn, extra iron was released, making the cells vulnerable.
  • In the human dopamine neurons, when the PHD enzyme was decreased, it led to a decrease in production of the ATP13A2 protein.  This in turn made the brain cells vulnerable.

What Does It Mean?

The researchers conclude that these two cell components — the enzyme and the gene — are linked. The enzyme PHD is responsible for controlling how much protein the ATP13A2 gene produces. In turn, the ATP13A2 gene (already linked to a rare form of PD) is crucial to the storage of iron in dopamine neurons.

In the future, therapies could be tested in laboratory models and in human trials to find out whether boosting the ATP13A2 gene could reduce iron levels in brain cells and potentially keep them safe.

These findings also suggest that age-related changes to brain cells’ lysosomes — and subsequent effect on their healthy balance of iron — may underlie PD more generally. In fact, mutations in ATP13A2 have been found in some people with “sporadic” PD — PD with no known cause. So a therapy targeted at ATP13A2 might be widely beneficial. But more research is needed.

Reference

Rajagopalan S, Rane A, Chinta SJ, and Andersen JK. (2016). Regulation of ATP13A2 via PHD2-HIF1a Signaling is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease. J Neuroscience 36(4): 1086-1095. DOI: 10.1523/JNEUROSCI.3117-15.201

Friday, March 3, 2017
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