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LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients
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LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients
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Journal Article
LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients
2019
Overview
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.
Mutations in
LRRK2
and
GBA1
, which encodes glucocerebrosidase (GCase), are associated with Parkinson’s disease. Here the authors show that LRRK2 is a negative regulator of lysosomal GCase activity, using dopaminergic neurons derived from iPSCs from PD patients with
LRRK2
mutations.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ alpha-Synuclein - metabolism
/ Dopamine
/ Dopaminergic Neurons - drug effects
/ Dopaminergic Neurons - enzymology
/ Dopaminergic Neurons - metabolism
/ Glucosylceramidase - genetics
/ Glucosylceramidase - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics
/ Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism
/ Mutation
/ Neurons
/ Parkinson Disease - enzymology
/ Parkinson Disease - genetics
/ Parkinson Disease - pathology
/ Science
