Genetic mutation common for Parkinson’s disease leads to poor localization of iron in the brain

Genetic mutation common for Parkinson’s disease leads to improper localization of iron in activated microglia, new study says Dec. 16e in the open access journal PLOS Biology, by Mark Cookson of the National Institute on Aging and colleagues. The findings may help explain the build-up of toxic iron in disease-affected areas of the brain and provide a basis for the development of therapies designed to correct the iron trafficking defect.

Mutations in the LRRK2 gene account for about 5% of all cases of familial Parkinson’s disease and about 1% of cases of non-familial disease. LRRK2 is a kinase, an enzyme that regulates other proteins by adding a phosphate group, and pathogenic mutations are known to increase the kinase activity of the enzyme.

One of the targets regulated by LRRK2 is called Rab8a, a protein which, along with many others in the Rab family, helps control the movement or “trafficking” of a wide variety of cell vesicles (linked subcellular compartments membrane). One of the tasks of Rab8a is to regulate the importation of iron into the cell via the transferrin receptor and to help recycle this receptor to the membrane after releasing the transferrin and the iron it carries.

To understand how LRRK2 mutations found in Parkinson’s disease might affect this process, the authors first visualized the movements of Rab8a in mouse astrocytes containing LRRK2 with a pathogenic mutation. They found that the mutant protein was responsible for redirecting Rab8a away from its normal location in the endocytic recycling compartment and sequestering it at damaged lysosomes.

This poor localization of Rab8a had a clear effect on the transferrin receptor: in cells containing normal LRRK2, the transferrin receptor was distributed among several types of vesicles. However, in cells containing the Parkinson’s mutant LRRK2, the transferrin receptor and its iron instead clustered in the same damaged lysosomes where Rab8a and the LRRK2 mutant were found.

This same poor localization of Rab8a receptors and transferrin has been observed in activated microglia derived from human cells carrying a pathogenic LRRK2 mutation. Microglia are a key contributor to inflammation in the brain. Finally, when mice carrying the same Parkinson’s mutation were exposed to a pro-inflammatory trigger, iron accumulated in the microglia of the striatum, a region of the brain that controls movement and is one of the parts of the brain most affected by Parkinson’s disease.

Our data suggest that a key step in the pathogenesis of Parkinson’s disease LRRK2 is the protein’s interaction with Rab8a and its subsequent effect on the mis localization of iron in activated microglia.. “

Mark Cookson, National Institute on Aging

Deposits of iron in the brain are a hallmark of Parkinson’s disease and other neurodegenerative diseases, and its build-up can lead to the production of free radicals and damage mitochondria, two steps considered critical in the disease cascade. “These results should help us understand the implications of blocking LRRK2 as a potential therapy for Parkinson’s disease.”

“Our study demonstrates altered iron regulation in models of Parkinson’s disease based on the LRRK2 gene,” adds Cookson. “Previous data has shown that iron can be deposited in the brain, which we now link to a known genetic cause of Parkinson’s disease that may be relevant for new treatments.”

Source:

Journal reference:

Mamais, A., et al. (2021) Mutations in LRRK2 linked to the sequestration of Parkinson’s disease Rab8a to damage lysosomes and regulate iron uptake by transferrin in microglia. PLOS Biology. doi.org/10.1371/journal.pbio.3001480.

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