PAK6 Activity as a Therapeutic Target in LRRK2-associated Parkinson's Disease

Study Rationale:
Mutations (changes) in the gene for the leucine-rich repeat kinase 2 (LRRK2) protein cause inherited Parkinson's disease (PD). Because the activity of LRRK2 is increased in such mutant proteins, drugs have been designed to reduce this activity with the intention of curing PD. However, it is unclear whether these drugs are safe for people because side effects have been observed in pre-clinical models. Thus, safer alternatives to drugs reducing the activity of LRRK2 are needed.

Hypothesis:
In the past, we found that LRRK2 works together with another protein called PAK6 to promote the growth of neurites, branches characterizing healthy nerve cells. Since neurites don't grow as well as they should in cells carrying LRRK2 mutations, in this study we will test the hypothesis that increasing the activity of PAK6 is beneficial in pre-clinical models of LRRK2-associated Parkinson's disease.

Study Design:
We will measure the activation of PAK6 as well as of other proteins that depend on the activity of PAK6 in the brains of pre-clinical models carrying LRRK2 mutations. Next, using gene therapy methods -- approaches that use genes instead of drugs -- we will evaluate whether increasing the activity of PAK6 in the brain is beneficial. In the latter study, we will use pre-clinical models with LRRK2 mutations and excess of alpha-synuclein -- a protein strongly implicated in PD -- in the brain.

Impact on Diagnosis/Treatment of Parkinson's disease:
If the results of these studies support the hypothesis that PAK6 has a protective effect in pre-clinical models of Parkinson's disease, this protein will represent a novel therapeutic target. We predict PAK6 to be safe given its restricted production in the brain and not in other organs or tissues.

Next Steps for Development:
Gene therapy is being effectively explored in pre-clinical and clinical studies of neurological and neurodegenerative disease. We envisage that gene therapy may be used to increase PAK6 activity in the brains of people with Parkinson's if this and, possibly, other pre-clinical studies clearly demonstrate the protective effect of this protein.