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Researchers identify the neurogenetic basis of excess iron in Parkinson’s disease.

It’s long been known that excess iron is found in the brains of patients with Parkinson’s disease (PD), an incurable neurodegenerative condition that affects motor function. However, the mechanism by which iron wreaks damage on neurons to cause PD is unclear. Now, a study from researchers at the Buck Institute shows that the damage stems from an impairment in the lysosome, the organelle that acts as a cellular recycling center for damaged proteins. The team state that it is this impairment which allows excess iron to escape into the neurons where it causes toxic oxidative stress. The research will be published online in The Journal of Neuroscience.

Previous studies show that 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.  With age, however, the ability of the lysosome to participate in autophagy becomes slower, resulting in the build-up of unrecycled non-protein ‘garbage’ within the cells. Less-than-optimal autophagy has been associated with several age-related diseases, including PD.  Recent studies have shown 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.  The mutation responsible for a rare early onset form of PD called Kufor-Rakeb syndrome was identified in 2010.  The current study shows that a mutation in a lysosomal gene associated with Kufor-Rakeb syndrome results in the toxic release of iron into the cell resulting in neuronal cell death.

The current study in both mice and cultured human dopaminergic cells, investigated a mutation in a gene (ATP13A2) associated with a rare early onset form of Kufor-Rakeb syndrome. Results show that when researchers knocked out ATP13A2 the lysosome was unable to maintain the balance of iron within the cell.  The lab state that mutations in this same gene have also been recently linked to sporadic forms of PD.

The team surmise that their findings suggest 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 PD.  For the future, the researchers state now there is a more specific target to allow them to selectively impact iron toxicity within the affected neurons.

Source: The Buck Institute for Research on Aging

 

Dopaminergic neurons in the human substantia nigra, the cells preferentially lost in Parkinson's disease. The yellow staining represents iron-dependent staining of the neurons.  Credit: Subramanian Rajagopalan, MSc. Buck Institute for Research on Aging.
Dopaminergic neurons in the human substantia nigra, the cells preferentially lost in Parkinson’s disease. The yellow staining represents iron-dependent staining of the neurons. Credit: Subramanian Rajagopalan, MSc. Buck Institute for Research on Aging.

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