Objective/Rationale:
Genetic testing of 3,500 Parkinson’s disease (PD) patients revealed that mutations in serum glucocorticoid-regulated kinase 1 (SGK1) gene reverts the risk of getting Parkinson’s disease associated with Leucine Rich Repeat Kinase 2 (LRRK2) mutations to that of the general population. In other words the SGK1 mutant protected LRRK2 mutants patients against PD. This study is designed to determine how SGK1 mutants protect LRRK2 mutants against PD.
Project Description:
The genes for the normal (wild type) and mutant (polymorphic) SGK1 and LRRK2 will be combined in neuronal cells to determine if the mutant SGK1 protects neuronal cells from cell death caused by the mutant LRRK2. These results will be compared to the wild type SGK1 and cell function will be monitored. Any differences in cell function or cell survival will be correlated. Since SGK1 is an enzyme it will be important to determine if the mutant causes the enzyme to work better or worse. We will also test to see if this mutant SGK1 can protect a pre-clinical model that has been treated with a neurotoxin that mimics PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Understanding how mutant SGK1 protects people with LRRK2 from getting PD by determining if this mutation causes the enzyme to work better or worse will enable us to devise strategies for developing inhibitors or activators that can be potential drugs to treat PD.
Anticipated Outcome:
Studies investigating the interaction between mutant SGK1 and mutant LRRK2 will help define if SGK1 is a good target for drug discovery to treat Parkinson’s disease and may help uncover other regulatory proteins which also may be new targets for drug discovery.
Final Outcome
Serum and glucocorticoid-regulated kinase 1, SGK-1, is an enzyme that plays and important role in neuronal cellular stress and therefore may be a new drug target for the treatment of Parkinson’s disease (PD). The goal of this project is to determine if SGK-1 expressed in the substantia nigra pars compacta (SNpc) can be protective against genetic defects, such as LRRK2:G2019S, and neurotoxins which cause neuronal cell death and may represent causes of non-genetic PD. The results showed that overexpression of SGK-1 in human dopaminergic cell lines was able to protect against LRRK2:G2019S-induced cell death. This suggests drugs aimed at activating SGK-1 may have the capacity to be neuroprotective. Tests are ongoing to see if SGK-1 can protect against neurotoxins in pre-clinical models.