Gladstone Institute

Investigating Mutant LRRK2 Toxicity in an In Vitro Neuronal Model

Research Area

Grant Type



Parkinson’s disease (PD), which afflicts more than 1 million people in the US alone, is a progressive neurodegenerative disorder that causes muscle tremor, stiffness, and weakness. PD leads to the progressive deterioration of nerve cells in a part of the brain called the substantia nigra (SN) and nerve cells within the SN and other parts of the brain contain protein aggregates, called Lewy bodies (LBs).

Mutations in the gene leucine-rich-repeat-kinase 2 (LRRK2) are the largest genetic cause of PD and mutations occur in familial and non-inherited cases. LRRK2 has been identified within LBs in PD patients with LRRK2 mutations, and overexpression of LRRK2 in cultured neurons leads to aggregates. LRRK2 has GTPase and kinase activities, but its functions in normal physiology and neurodegeneration are unknown.

We propose to develop a primary neuronal model to define the role of LRRK2 GTPase and kinase activity, expression levels, and aggregate formation in the survival of nerve cells. We will use an automated microscope, developed in our laboratory, to follow the fate of many individual neurons over time. Using this approach, we will define the relationships between aggregate formation, LRRK2 expression levels, and the ultimate fate of the cell, which are very difficult with conventional microscope analysis. Understanding whether LRRK2 activity and aggregates are beneficial, incidental, or detrimental to neurons will be valuable to the rational design of future therapies.