How the Parkinson´s kinase LRRK2 regulates the endo-lysosomal and innate immune systems

Innate immunity – the ability to sense and rapidly respond to danger, requires tight control to avert self-destruction.

We are interested in the mechanisms that underlie this regulation and how the breakdown in such regulation impacts the outcome of infections and inflammatory diseases. The endo-lysosomal system is best known as a network of vesicles that target particles for degradation and recycling.

However, accumulating evidence, including from my lab, demonstrates that the endo-lysosomal system is also a hub for innate immune signaling regulation.

Recently, we have identified the Parkinson´s associated kinase, LRRK2, as a key new regulator of the endo-lysosomal and exosome secretion pathway. Further, we established that a gain-of-function in LRRK2 kinase results in spontaneous inflammation in humans and mice.

The goal of this project is to investigate how LRRK2 regulates the endo-lysosomal, exosomal, and innate immune systems and its potential as therapeutic target for shaping the outcome of viral infections, age-associated chronic inflammation and neurodegeneration.

These tasks will be tackled by employing a multidisciplinary approach that combines proteomics, functional genomics, biochemical tools, as well as new transgenic mouse models. This project is organized into three distinct aims to be implemented concurrently over a period of five years.