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Funded Studies

Studying How Defects in Autophagy Contribute to the Aggregation of Alpha-synuclein in Neurons with LRRK2 Mutations

Study Rationale: Mutations in the LRRK2 gene are the most frequent cause of inherited forms of Parkinson’s disease (PD). We have found that these mutations disrupt autophagy—a process that cells deploy to degrade intracellular waste, including damaged and misfolded proteins. In this study, we will investigate how LRRK2 mutations impair autophagy and assess how defects in autophagy can lead to the death of neurons in PD.

Hypothesis: We hypothesize that LRRK2 mutations disrupt autophagy by enhancing the phosphorylation of Rab, a family of proteins involved in regulating intracellular trafficking, leading to impaired degradation of the toxic protein alpha-synuclein.

Study Design: We will conduct microscopic studies of autophagy in isolated mouse and human neurons. Because Rab proteins are targets of the LRRK2 protein, we will investigate whether the effect that LRRK2 mutations have on autophagy is mediated by Rab proteins—and which specific Rab protein is responsible. Further, we will assess whether defects in autophagy lead to impaired degradation of alpha-synuclein, resulting in the buildup of toxic protein clumps. Comparing the results from mouse and human neurons will allow us to test the consistency of our findings.

Impact on Diagnosis/Treatment of Parkinson’s disease: Positive findings would further support the development and clinical tests of drugs that decrease the activity of LRRK2 protein. In addition, our study may open an avenue toward a more specific therapeutic approach for LRRK2-mediated PD.

Next Steps for Development: Our study will investigate how impairment of autophagy caused by LRRK2 mutations is tied to neuronal cell death. If our findings are consistent, we will investigate whether neurons from people with forms of PD that do not involve LRRK2 have similar defects in autophagy and alpha-synuclein degradation.


  • Clemens-Alexander Boecker, MD

    Goettingen Germany

  • Erika L.F. Holzbaur, PhD

    Philadelphia, PA United States

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