The Role of LRRK2 in Neuronal Calcium Maintenance
Target Validation Pilot Award, 2016
Calcium is essential for neuronal survival and function. Flawed intracellular calcium homeostasis (maintenance) is linked to neurodegeneration. There is, however, a major knowledge gap in understanding the mechanisms of neuronal calcium control and Parkinson's disease (PD) pathology. Our preliminary data show dysregulation of calcium homeostasis, reduced endoplasmic reticulum (part of the cell that makes proteins and fats; ER) stress response and neurite (neuron projection) collapse after ER stress in induced pluripotent stem cell (man-made stem cells that can become different types of cells; iPS)-derived LRRK2 G2019S (a specific LRRK2 mutation) neurons.
We hypothesize that the LRRK2 G2019S mutation dysregulates intracellular calcium homeostasis, an effect that could contribute to PD development.
We propose to study the mechanisms causing dysregulation of calcium homeostasis induced by the LRRK2 G2019S mutation. Using live calcium imaging techniques, we will investigate LRRK2 function in calcium homeostasis in human iPS-derived neurons from those carrying the LRRK2 G2019S mutation. To further determine this mechanism, we will use a combination of calcium imaging and electrophysiological (electrical signals in the brain) studies and identify key calcium channels, transporters and sensors influenced by the LRRK2 G2019S mutation. We will use two control groups for these experiments: control neurons and neurons treated with antisense oligonucleotides (man-made chemicals) specific for the LRRK2 G2019S mutation.
Impact on Diagnosis/Treatment of Parkinson's Disease:
The proposed project will address how the LRRK2 G2019S mutation changes intracellular calcium regulation. Through these studies, we may identify a potential target that can reestablish calcium homeostasis, directly rescuing ER stress response and neurite collapse.
Next Steps for Development:
As a future direction of this study, we will aim to normalize the ER stress response and prevent neurite collapse in neurons carrying the LRRK2 G2019S mutation. Collectively, these data may highlight new pharmacological targets for PD.
Professor of Neurology and Neuroscience at Harvard Medical School
Director of the Neuroregeneration Research Institute at McLean Hospital
Location: Boston, Massachusetts, United States
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