Study Rationale:
Earlier work from this group reported greater LRRK2 activity in people with idiopathic (cause unknown) Parkinson’s. This project builds on those findings to investigate how that increased activity may lead to Parkinson’s disease (PD). Deficits in the glucocerebrosidase (GCase) protein also occur in the brains of people with PD. LRRK2 is implicated in lysosomal degradation (the cell’s garbage disposal). This study will examine whether increased LRRK2 kinase activity is central to deficits in GCase by causing lysosomal dysfunction.
Hypothesis:
We hypothesize that deficits in GCase activity in idiopathic PD patients is caused by overall lysosomal dysfunction. Increased LRRK2 kinase activity may impair lysosomal trafficking (in part through excessive phosphorylation of the early endosomal protein Rab5).
Study Design:
In this study, we will determine whether inhibition of LRRK2 kinase activity can prevent lysosomal dysfunction and preserve GCase function. Next, we will test whether a LRRK2 inhibitor drug can prevent lysosomal dysfunction and degeneration in a model of idiopathic PD. Lastly, we will determine whether Rab5-positive early endosomes accumulate in idiopathic PD brains and correlate with other measures of lysosomal impairment.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Completion of these experiments has the potential to shift how idiopathic PD patients are treated. If we are correct and increased LRRK2 activity impairs lysosomal function and causes GCase deficits in PD, LRRK2 inhibitors may be beneficial to the greater population of PD patients.
Next Steps for Development:
Expand the therapeutic potential of LRRK2 inhibitors to the broader population of idiopathic PD patients.