Variant in LRRK2, Tied to Disease, Affects Gene’s Activity in Microglia

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A Parkinson’s-associated variant in the LRRK2 gene affects the gene’s activity in a single group of brain cells: microglia, the resident immune cells of the brain.

“Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis [development],” the researchers wrote.

The study, Association of a common genetic variant with Parkinson’s disease is mediated by microglia,” was published in Science Translational Medicine.

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The causes of Parkinson’s remain incompletely understood, but genetics are known to play a role in determining disease susceptibility. One of the disease’s most closely linked genes is LRRK2; numerous variations in this gene have been tied to altered Parkinson’s risk.

Many Parkinson’s-related variants in LRRK2 are located in the protein-coding part of this gene. However, a most strongly associated variant is at a location dubbed rs76904798, just before the part of the gene that actually provides instructions for making a protein.

LRRK2 variant affects DNA sequences, Parkinson’s risk

Most people have the nucleotide cytosine (“C”) at this location, but others have a thymine (“T”) that is associated with increased Parkinson’s risk. Since everyone has two copies of the LRRK2 gene — one inherited from each biological parent — a given cell can have a genotype of “CC,” “CT,” or “TT” at this location.

Of note, nucleotides are the building blocks of DNA, and gene variants describe any change in the nucleotides, or DNA sequences, that compose a gene.

How these genetic differences might influence LRRK2 gene activity has been obscure. Here, a team led by scientists at the National Institute on Aging conducted a series of experiments to learn more.

In an initial analysis, the researchers analyzed gene expression data in brain cells collected by the North American Brain Expression Consortium. Gene expression basically measures how much individual genes are “turned on or off” — meaning they are expressed (“on”) and translated into products like molecules and proteins, or they are not (“off”) — and to what degree. Data on 117,632 individual cells, spanning all of the different types of brain cells, were in the analysis.

Expression of the LRRK2 gene was seen to be significantly higher in microglia with the Parkinson’s-associated “TT” variant at rs76904798, compared to cells with the “CC” variant. Other cell types showed no changes in LRRK2 expression based on the rs76904798 variant.

“Therefore, we find a correlation between [Parkinson’s] risk nominated by rs76904798 and LRRK2 expression only in microglia,” the researchers wrote.

Lab dish experiments using stem cell-derived microglia yielded similar results, with microglia harboring the Parkinson’s-associated variant showing higher LRRK2 gene expression, higher activity of the protein encoded by that gene, and increased inflammatory activity. Notably, altering two other Parkinson’s-associated regions in the LRRK2 gene, rs76904798 with the “CT” variant and rs1491942, did not influence the rs76904798 variant’s demonstrated effect on the gene’s activity in microglia.

When a gene like LRRK2 is “read,” molecular machinery inside of the cell has to physically interact with chromatin — the strands of DNA housing the gene. In further experiments, the scientists demonstrated that, in microglia housing the Parkinson’s-associated variant, the chromatin region containing the LRRK2 gene is more open and easily accessible to these DNA-reading molecular machines.

“We hypothesize that the open chromatin regions in microglial DNA allow for the regulation of LRRK2 expression distinct from basal expression in different cells,” the researchers wrote. “By extension, this suggests that there may be differences in the function of LRRK2 in different cell types in the human brain.”

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