Although Parkinson’s disease (PD) causes are in most cases unknown (idiopathic) some cases are linked to a person’s genetics. Leucine-rich repeat kinase 2 (LRRK2) is a very important genetic contributor to PD and its over-activation may also play a role in non-genetic causes of PD. Therefore, therapies that block LRRK2 may represent effective treatments for many PD patients. How LRRK2 promotes PD is not fully understood, however we have shown that it activates a family of proteins called Rabs and these proteins are likely to be involved in causing PD. Importantly, we have identified the protein phosphatase (PPM1H) that is responsible for switching off LRRK2-mediated activation of Rab.
Increasing PPM1H function with small molecules (drugs) will suppress LRRK2 function and could be used to treat PD.
We will develop different assays to screen large numbers of small-molecule compounds in order to identify those that have the ability to increase the activation of PPM1H.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Activators of PPM1H can be further developed into drugs that are safe to give to people with PD. This would reverse the effect of LRRK2 over-activity and treat the disease. Importantly this is likely to be therapeutically beneficial to a large amount of PD patients (idiopathic and genetic).
Next Steps for Development:
Small-molecule compounds identified in our assays will need to be optimized so that they can enter cells (cell-permeable) and exhibit drug-like properties (for example: soluble, potent and stable) that can be tested in models of Parkinson’s disease.