LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients

Daniel Ysselstein; Maria Nguyen; Tiffany J. Young; Alex Severino; Michael Schwake; Kalpana Merchant; Dimitri Krainc

doi:10.1038/s41467-019-13413-w

LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients

Daniel Ysselstein, Maria Nguyen, Tiffany J. Young, Alex Severino, Michael Schwake, Kalpana Merchant, Dimitri Krainc^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

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.

Original language	English (US)
Article number	5570
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13413-w
State	Published - Dec 1 2019

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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title = "LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson{\textquoteright}s disease patients",

abstract = "Mutations in LRRK2 and GBA1 are common genetic risk factors for Parkinson{\textquoteright}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.",

author = "Daniel Ysselstein and Maria Nguyen and Young, {Tiffany J.} and Alex Severino and Michael Schwake and Kalpana Merchant and Dimitri Krainc",

note = "Funding Information: We thank the Northwestern University Stem Cell Core Facility for the generation of the iPSC lines. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. D.Y. was supported by NIH grant T32NS041234, M.N. was supported by NIH grant 2T32AG020506–16, M.S. received a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft (DFG) and D.K. was supported by NIH grants R01 NS076054, R37 NS096241, and a grant from the Michael J. Fox Foundation Parkinson{\textquoteright}s Research (D.K. and K.M.). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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AU - Schwake, Michael

AU - Merchant, Kalpana

AU - Krainc, Dimitri

N1 - Funding Information: We thank the Northwestern University Stem Cell Core Facility for the generation of the iPSC lines. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. D.Y. was supported by NIH grant T32NS041234, M.N. was supported by NIH grant 2T32AG020506–16, M.S. received a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft (DFG) and D.K. was supported by NIH grants R01 NS076054, R37 NS096241, and a grant from the Michael J. Fox Foundation Parkinson’s Research (D.K. and K.M.). Publisher Copyright: © 2019, The Author(s).

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N2 - 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.

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LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients

Abstract

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