My PD Story

2025 Trailblazer Award

Investigating How the Puzzling G2385R LRRK2 Mutation Leads to Parkinson’s

While aging and environmental factors are the greatest contributors to developing Parkinson’s disease (PD), Parkinson’s Foundation research has found that approximately 13% of people with Parkinson’s have a known genetic link to the disease. For those people, a small change in their DNA (a DNA variant) contributes to PD-associated cellular disruptions.

Variants of the gene that create a protein called Leucine-Rich Repeat Kinase 2 (LRRK2) are found in 1-5% of all PD cases. Significant progress is being made to understand how LRRK2 variants lead to PD, but some variants are more complicated than others, leaving gaps in our scientific understanding.

Patrick Lewis, PhD, recipient of a Parkinson’s Foundation Trailblazer Award, is devoting his research to one perplexing LRRK2 variant called G2385R. This variant affects a different area of the LRRK2 protein than other more well-studied variants. Interestingly, the effects of the G2385R variant on cell function may be the opposite of other LRRK2 variants, raising questions about how it leads to PD.

Decoding Gene Variant Naming

Scientists use a specific alphanumeric pattern to name genetic variants, which commonly goes letter-number-letter. The first letter and number refer to an amino acid — building blocks of proteins — at a specific position in a protein blueprint chain. The second letter refers to what the variant changes the original amino acid into, potentially affecting the function of the protein. For G2385R variants, the uncharged glycine (G) in the 2385^th amino acid slot in the chain to build LRRK2 becomes a charged arginine (R) instead.

From his lab at the Royal Veterinary College in London, UK, Dr. Lewis is preparing a wide range of experiments to fully understand how G2385R LRRK2 operates within cells and how it contributes to PD. First, he and his team will observe the biochemical activity of the variant protein, comparing and contrasting its functionality to both original LRRK2 and other LRRK2 variants.

They will then monitor how the variant LRRK2 reacts to biological stress within the cell, where it moves and accumulates and how that disrupts other pathways and processes. Finally, Dr. Lewis will test how various drugs, including LRRK2 inhibitors currently undergoing clinical trials, impact G2385R LRRK2, providing insight into potentially useful therapeutics in the future.

The G2385R LRRK2 variant is more common in east Asia than in Europe or America, affecting nearly 2% of people with PD across countries including China, Japan and Korea. Understanding the disease association of this variant will go a long way in advancing treatments not just for those hundreds of thousands of people with the G2385R variant, but for all those with LRRK2 variants as our scientific understanding of the whole protein increases.

When asked about what this support means to him and his work, Dr. Lewis said, “Receiving a Trailblazer Award from the Parkinson's Foundation is really an honor. This project will allow me to develop a new avenue of research investigating LRRK2 to understand how one of the most common Parkinson's risk variants worldwide can increase the likelihood of developing Parkinson's at a functional level.”

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