Study Rationale:
Individuals with genetic variations or mutations in a gene called LRRK2 are at increased risk of developing Parkinson’s disease (PD). Because these alterations enhance the activity of the LRRK2 protein, it should be possible to discover drugs that can counteract the effects of the mutations by eliminating LRRK2 activity, thus preventing the development of PD. Although much effort has focused on developing drugs that target the portion of the protein that houses its enzymatic activity, we propose to target a segment that is required for LRRK2 proteins to come together to form a functional complex.
Hypothesis:
Our hypothesis is that targeting the WD domain that allows LRRK2 to form a functional dimer could facilitate the development of a novel class of PD therapeutics.
Study Design:
In our studies of cancer, we have been developing new artificial intelligence and screening technologies specifically for a structure called a WD domain. WD domains are found in many proteins, including LRRK2, where they promote protein-protein interactions. Using our tools and expertise, we will identify small molecules that bind to the WD domain in LRRK2, disrupting the formation of functional protein dimers and inhibiting LRRK2 activity.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We intend to make our discoveries and drug candidates freely available to the research community, enabling rapid progress toward their development into new treatments for PD.
Next Steps for Development:
If successful, we would continue to develop our candidate molecules to produce an effective drug that can also be used to examine the role of LRRK2 and its WD domain in the biology of PD.