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Targeting Retromer Dysfunction: A Convergent Mechanism in Familial and Sporadic Parkinson’s Disease

Study Rationale:                   
Our goal is to understand how mutations in the gene LRRK2 can drive Parkinson’s disease (PD) risk. Our previous studies of neurons with mutant LRRK2 kinase have pointed to defects in the cellular machinery that traffics cell-surface proteins towards a variety of intracellular destinations. This machinery plays an essential role in determining whether cargo proteins are sent off for disposal or recycled. We have developed a variety of tools that aim not only at detailing the cellular defects associated with LRRK2 mutations, but also at determining whether we can rescue such defects using drug-like reagents.  

We hypothesize that LRRK2 mutations lead to PD due to inappropriate and defective trafficking of proteins between different compartments within neurons.

Study Design:
We will dissect each step in the trafficking of proteins within neurons that carry LRRK2 mutations, with a focus on pathways that relate to the disposal of proteins. Using genetic as well as drug-like reagents, we will attempt to pinpoint potential therapeutic targets, and test whether manipulating these targets alleviates cellular defects in the context of LRRK2. 

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
The goal of this work is to pinpoint the cellular trafficking defects in neurons that harbor LRRK2 mutations, and thus identify potential new drug targets.

Next Steps for Development:
Our preliminary studies suggest that the trafficking-related defects in LRRK2 mutant neurons are potentially amenable to drug-like treatments. Thus once the targets are clearly established, the next step would be to generate selective drugs that improve trafficking and are safe.


  • Scott A. Small, MD

    New York, NY United States

  • Dagmar Ringe, PhD

    Waltham, MA United States

  • Asa Abeliovich, MD, PhD

    New York, NY United States

  • Gregory Petsko, DPhil

    New York, NY United States

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