Studying the Effect of p62 on the Toxicity of LRRK2 in the Brain

Study Rationale:
Mutations (changes) in the LRRK2 gene are a leading genetic cause of Parkinson's disease (PD). They cause dysfunction in the LRRK2 protein, making it toxic to the brain. Protein LRRK2 interacts with many other proteins, one of which is p62. Found in protein clumps called Lewy bodies in PD, p62 is also involved in several other neurological diseases. We have identified exactly which part of p62 interacts with LRRK2 and determined several structural elements of p62 and LRRK2 that are necessary for this interaction. When the interaction of p62 and abnormal, PD-associated LRRK2 takes place, the latter becomes even more toxic to the brain.

Hypothesis:
We hypothesize that p62 can interact with LRRK2 and increase its activity as well as the toxicity of PD-associated LRRK2.

Study Design:
In this study, we will develop novel reagents to detect LRRK2 interaction with p62. We will then determine how p62 activates LRRK2 and how the modification of p62 by LRRK2 changes its function. To establish a clinical connection, we will analyze the levels of p62 and the LRRK2 modification site in biosamples donated by people with PD.

Next Steps for Development:
Phosphoantibodies against p62 -- molecules that can bind to p62 specifically -- could bring value as biomarkers (objective measures) of PD. The interactions of LRRK2 and p62 with other molecules are diverse and important to cell survival and response to stress. Of these, interactions relevant to Parkinson's hold key to understanding the disease and developing new therapeutics.