Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. Importantly, inhibition of the kinase activity of LRRK2 is now entering clinical trials and so it is critical to understand what the biological consequences of inhibited activity is, which we have approached using both genetic and pharmacological tools. Related to the above, many pieces of data suggest that under endogenous conditions, LRRK2 shows only low basal activity. We have developed a strong interest in how LRRK2 activity is regulated in cells and have seen that lysosomal damage is a strong trigger for LRRK2 activation, as measured by phosphorylation of RAB proteins and their accumulation at the lysosomal membrane. Using specific lysosomal stimuli, we also find that the lysosomal membrane can form narrow tubules that separate off from the parent lysosome and are transported to active lysosomes within the same cell. This process, which we have named lysosomal tubulation/sorting driven by LRRK2 (LYTL) depends on tyrosinated microtubules for transport and the endoplasmic reticulum for scission of tubules. Furthermore, the positioning of the lysosome is important for control of phosphorylation of some RAB proteins, with perinuclear lysosomes showing stronger pRAB10 than more peripheral organelles. This implies that responses to lysosomal damage and transport are likely co-regulated in cells.