Abstract
Mutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). Here we describe a mechanistic and therapeutic convergence of LRRK2 and GCase in neurons derived from patients with PD. We find that GCase activity was reduced in dopaminergic (DA) neurons derived from PD patients with LRRK2 mutations. Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. This increase is sufficient to partially rescue accumulation of oxidized dopamine and alpha-synuclein in PD patient neurons. We have identified the LRRK2 substrate Rab10 as a key mediator of LRRK2 regulation of GCase activity. Together, these results suggest an important role of mutant LRRK2 as a negative regulator of lysosomal GCase activity.
Highlights
Mutations in leucine rich repeat kinase 2 (LRRK2) and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase)
We have recently shown that human DA neurons differentiated from induced pluripotent stem cells exhibit pathological phenotypes such as accumulation of oxidized dopamine products and neuromelanin that are observed in PD autopsied brain tissue but not seen in mouse models[19]
We examined GCase activity in DA neurons derived from PD patients and found that LRRK2 mutations result in reduced lysosomal GCase activity
Summary
Mutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson’s disease (PD) and major efforts are underway to develop new therapeutics that target LRRK2 or glucocerebrosidase (GCase). Inhibition of LRRK2 kinase activity results in increased GCase activity in DA neurons with either LRRK2 or GBA1 mutations. These patients developed PD symptoms at an earlier age compared to carriers of only LRRK2 or GBA1 mutations[22,23,24] Based on these observations, we hypothesized that GBA1 and LRRK2 mutations may contribute to PD pathogenesis through a common biological pathway. We hypothesized that GBA1 and LRRK2 mutations may contribute to PD pathogenesis through a common biological pathway To test this hypothesis, we examined GCase activity in DA neurons derived from PD patients and found that LRRK2 mutations result in reduced lysosomal GCase activity. These findings could have significant therapeutic implications for these patient populations as therapeutic compounds targeting either LRRK2 or GCase are currently in clinical trials
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
