LRRK2 mutations drive iron accumulation in genetic Parkinson’s disease

Reuters Health - 23/12/2021 - Mutations in LRRK2 seem to drive the mislocation and accumulation of toxic iron in the brains of individuals with genetic Parkinson's disease (PD), researchers suggest.

Mutations in LRRK2 account for about 5% of all cases of familial PD and about 1% on non-familial cases.

"We describe a series of molecular links between a known cause of Parkinson's disease, LRRK2 mutations, with changes in iron metabolism in the context of inflammation," Dr. Mark Cookson of the US National Institute on Aging, National Institutes of Health in Maryland told Reuters Health by email. "It has been known for some time that inflammation and iron accumulation occur in the Parkinson's brain but our study is the first to outline the specific links to LRRK2."

"One area that was surprising was that we saw such clear-cut effects of mutations when we looked in the mouse model," he said. "These animals generally don't show phenotypes so being able induce strong changes was quite striking."

"Right now," he added, "there are multiple clinical trials focused on lowering the activity of LRRK2 in people with PD and our work is supportive of that treatment as a valid approach rather than suggesting new directions."

LRRK2 regulates, among other proteins, Rab8a, which is involved in the regulation of iron import into cells via the transferrin receptor, and recycling that receptor back to the membrane after it releases transferrin, the team explains in PLOS Biology.

To understand how LRRK2 mutations might affect this process, the authors first visualized Rab8a movements in mouse astrocytes containing pathogenically mutated LRRK2, and found that the mutant protein redirected Rab8a away from its normal location at the endocytic recycling compartment, instead sequestering it at damaged lysosomes.

Rab8a mislocation had a clear effect on the transferrin receptor: in cells containing normal LRRK2, the receptor was distributed among multiple vesicle types.

By contrast, in cells containing mutant LRRK2, the transferrin receptor and its iron instead clustered at the same damaged lysosomes where Rab8a and mutant LRRK2 were found.

The team observed the same mislocalization of Rab8a and transferrin receptors in activated microglia derived from human cells carrying a pathogenic LRRK2 mutation.

Further, when mice carrying the same LRRK2 mutation were exposed to a proinflammatory trigger, iron accumulated in microglia in the striatum, a region of the brain that controls movement and is affected in Parkinson's disease.

The authors conclude, "Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia."

Dr. James Beck, Senior Vice President and Chief Scientific Officer of the Parkinson's Foundation in Miami, commented on the study in an email to Reuters Health. "The implications of this study are broad. First, this provides a plausible biological mechanism identifying why a mutation in the LRRK2 gene might lead to people to develop PD."

"Second," he said, "this study provides a reason to examine previous research linking iron accumulation and PD. The implication extends beyond genetic forms of PD."

"We know from previous research that even people without mutations in LRRK2 may make too much LRRK2 protein," he continued. "If this link between LRRK2 and iron accumulation holds, we may now have a basis for why many people may develop idiopathic PD. Therefore, because of the potential significance of these findings, replication is needed to confirm these conclusions. This could suggest how a mutation in this gene could lead to PD as well as how PD could occur spontaneously."

The foundation will soon embark on a set of clinical trials of PD therapeutics targeting the LRRK2 enzyme, he added.

SOURCE: https://bit.ly/3qEc7Fx PLOS Biology, online December 16, 2021

By Marilynn Larkin



Posted on 23 December 202117 January 2022