Rab GTPases, a family of small molecules that guide protein movement around cells, are linked to Parkinson's disease (PD). We have identified a group of Rabs with potential roles in stimulating protein clearance and degradation (break down). Here, we will evaluate whether these Rabs can stimulate the degradation of alpha-synuclein, a protein whose accumulation and aggregation (clumping) contributes to the development of PD.
We hypothesize that specific Rab GTPases will stimulate the clearance of alpha-synuclein from sites of contact between neurons (called synapses) and thereby prevent defects in neuronal communication that occur in PD from alpha-synuclein clumping.
We will measure the clearance and degradation of alpha-synuclein in cells using different biochemistry and microscopy methods. We will evaluate whether the expression of specific Rab GTPases can stimulate alpha-synuclein degradation. For any such Rabs, we will use imaging methods to investigate whether their expression in neurons can rescue defects in communication that result from accumulation of alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson's disease:
This study will identify Rabs that stimulate alpha-synuclein degradation and assess whether they can rescue defects in synapse function caused by alpha-synuclein buildup. Any Rabs with these properties could be targeted by screening for chemical compounds that stimulate their activity.
Next Steps for Development:
If Rabs are identified in this study, the next step will be to test whether their expression in dopamine neurons in the brain (using a virus for delivery) can rescue neurological and behavioral defects in alpha-synuclein pre-clinical models of PD.