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Studying LRRK2 Mutations as a Possible Cause of Waste Buildup in Nerve Cells

Study Rationale:
Health and longevity of brain cells depends on the efficiency of their waste removal process, known as autophagy or self-eating. Cells use autophagy to get rid of unwanted protein clumps and broken mitochondria -- cell's energy generators -- among other waste. Accumulation of damaged mitochondria and protein clumps inside the cell are a hallmark of neurodegenerative diseases, such as Parkinson's disease (PD), suggesting a defect in autophagy as a cause of PD. Recent discoveries in the field of genetics support this possibility.

We hypothesize that mutations (changes) in the LRRK2 gene -- a leading genetic cause of PD -- disrupt autophagy, causing the accumulation of damaged mitochondria and/or protein clumps in nerve cells.

Study Design:
We will study autophagy in nerve cells in real time under the microscope, comparing observations in cells with or without mutations in the LRRK2 gene. We predict that disease-associated mutations in LRRK2 will disrupt autophagy. If so, we will try to reverse this disruption with a drug that deactivates LRRK2. We will perform these studies in nerve cells isolated from pre-clinical models and also in human nerve cells to test the consistency of our findings. If they are indeed consistent, then we will perform similar studies in nerve cells donated by people with non-inherited Parkinson's to further confirm our observations.

Impact on Diagnosis/Treatment of Parkinson's disease:
Positive results of these studies would strongly implicate defects in autophagy as the cause of neurodegeneration in PD and would further support the development of therapies focused on controlling the activity of the LRRK2 protein.

Next Steps for Development:
If deactivation of LRRK2 restores the ability of neurons to dispose of their waste by means of autophagy, then this would open an avenue toward a more specific therapeutic approach.


  • Erika L.F. Holzbaur, PhD

    Philadelphia, PA United States

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