Research Snapshot: Drs. Rebecca Wallings and Malú Gámez Tansey

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Given the critical role of antigen presentation, lysosomal function and cytokine release in macrophages, it is likely LRRK2-targetting therapies may have therapeutic value with regards to mutant LRRK2 but deleterious effects on the peripheral immune system, such as altered pathogen control and infection resolution.

By Michelle Jaffee

New mouse-model research led by University of Florida neuroscientists at the McKnight Brain Institute offers insights into potentially positive and negative effects of changing expression levels of a gene associated with increased risk of developing Parkinson’s disease.

Levels of the LRRK2 gene are widely under investigation as an appealing target for Parkinson’s therapies, moving towards clinical trials. In the new preclinical study, researchers focused on the Parkinson’s-associated G2019S mutation in the LRRK2 gene, examining whether reducing its expression in immune cells would affect critical immune responses.

The study, published in the journal Molecular Therapy Nucleic Acids by Cell Press, was led by Rebecca Wallings, D.Phil., a postdoctoral fellow in the department of neuroscience, and senior author Malú Gámez Tansey, Ph.D., the Norman and Susan Fixel Professor of Neuroscience and Neurology. The study was a collaborative effort with industry partners at Biogen and Ionis Pharmaceuticals, who provided the antisense oligonucleotides that were used to target and reduce LRRK2 expression in the immune cells.

LRRK2 is thought to possibly play a key role to peripheral immunity, and the team examined whether targeting increased LRRK2 levels in peripheral immune cells would be beneficial or harmful.

To do so, they studied macrophages, cells often found at sites of infection, in mice with the genetic mutation. Using multicolor flow cytometry, imaging-based assays and RNAtranscriptomic profiling to quantify macrophage function, they altered levels of gene expressionusing antisense oligonucleotides, a therapeutic strategy that has recently moved towards clinical trials in humans.

The team found that the genetic mutation increased formation of tubular structures from the lysosome, a membrane-bound structure involved in various cell processes, and demonstrated thatreducing LRRK2 expression decreased release of cytokines, proteins that affect inflammation in the body. Reduced LRRK2 expression also decreased the formation of lysosomal tubules responsible for antigen presentation, a function critical for communication between macrophages and T cells and subsequent resolution of infections and inflammation.

They concluded it is likely that LRRK2-targeting therapies with systemic activity may have therapeutic value for the mutation but harmful effects on the peripheral immune system, and they suggested this should be considered when reducing levels of LRRK2 without the mutation.

It will be crucial to next establish if these LRRK2-targeting therapies have deleterious effects on immune functions such as pathogen control in in vivo models, and further establish how altering macrophage function via LRRK2-targeting therapies affects communication between different immune cell subsets,” Wallings said. 

Read the paper in Molecular Therapy Nucleic Acids.