The many faces of LRRK2: a friend turned foe

LRRK2 is involved in several important cellular processes, not just autophagy. Research into its role in inflammation is now implicating LRRK2 in idiopathic forms of the condition as well. LRRK2 overactivation may confer protection from infection early in life, but increase the risk for Parkinson’s later on. Establishing that LRRK2 inhibitors are first of all safe and well tolerated in people with Parkinson’s is the essential next step.

Disease modifying efforts focusing on LRRK2 may have significant implications for many more people with Parkinson’s, not just those 1-2% with the genetic form.

LRRK2 is one of the genes that causes familial forms of Parkinson’s. It codes for a large protein, a part of which functions as an enzyme called a kinase. Its role is to activate other proteins within the cell involved in autophagy, the process of appropriately degrading and recycling cellular machinery. Heritable LRRK2 mutations lead to overactivation of this kinase, so in terms of disease modification, efforts are focusing on developing an effective inhibitor.

But there is a lot of emerging evidence that this large protein carries more important functions in the cell beyond autophagy, pointing to its role more generally in Parkinson’s, not just rare genetic forms.

LRRK2 has a direct effect on a group of substances called RAB proteins. These are involved in making the small sac-like structures called vesicles which contain substances trafficked around in the cell. This is especially important for the cells of the immune system where LRRK2 is involved in the formation of the inflammasome: this is a complex of different proteins which need to be shuttled around and come together to produce inflammatory signals.

Animal studies are now showing us that mutant LRRK2 (which is always overactive) promotes inflammation necessary for immune defense early in life, protecting the body from infection before Parkinson’s strikes. However, later in life, this increases the risk for Parkinson’s. This phenomenon is known as antagonistic (ie. opposing) pleiotropy (ie. multiple functions).

Several pharmaceutical companies are developing LRRK2 inhibitors. But adverse effects of LRRK2 inhibitors from animal studies include damage to the kidney and lung, so close monitoring is essential in any future trial in humans. Given LRRK2’s role in immune function, an important open question remains whether LRRK2 inhibitors increase susceptibility to infections. Carefully planned clinical trials in people with Parkinson’s are necessary to establish whether LRRK2 inhibition is both safe and carries disease modifying potential.

CPT work in this area

Read another summary on LRRK2, Crohn’s and Parkinson’s