Studies on the Modifying Effect of Mutant LRRK2 on Mutant GBA1 that Controls Severity of Parkinson Disease in Drosophila Models

In the present proposal we will address how the genetic interplay between mGBA1 and mLRRK2 affects PD severity. The specific aims are:
 

1. Generalize the interaction between mGBA1 and mLRRK. We have shown the interplay between mGBA1 and mLRRK2 using I2020T and G2019S mLRRK2 variants and L444P and N370S mGBA1 variants. We would like to use other mGBA1 variants which are important in the study of PD: E326K and R496H. We also wish to test a mutation in the SMPD1 gene, associated with Neimann-Pick disease, and with PD.
    
2. Study ERAD, UPR and the behavioral consequences of the different mutation combinations. We would like to confirm the amelioration of ERAD and UPR in the double mutant flies due to the protective effect of mLRRK2. We also wish to establish behavioral changes associated with PD, like: loss of smell and loss of cognition.
    
3. Study the molecular mechanisms underlying the interplay between mGBA1 and mLRRK2. We will test which is the mechanism underlying the increased mLRRK2-mediated degradation of mGCase. Whether it is proteasoml- or autophagy-related mechanism.