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

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  • Daniel Ysselstein

    (Northwestern University Feinberg School of Medicine)

  • Maria Nguyen

    (Northwestern University Feinberg School of Medicine)

  • Tiffany J. Young

    (Northwestern University Feinberg School of Medicine)

  • Alex Severino

    (Northwestern University Feinberg School of Medicine)

  • Michael Schwake

    (Northwestern University Feinberg School of Medicine)

  • Kalpana Merchant

    (Northwestern University Feinberg School of Medicine)

  • Dimitri Krainc

    (Northwestern University Feinberg School of Medicine)

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.

Suggested Citation

  • Daniel Ysselstein & Maria Nguyen & Tiffany J. Young & Alex Severino & Michael Schwake & Kalpana Merchant & Dimitri Krainc, 2019. "LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson’s disease patients," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13413-w
    DOI: 10.1038/s41467-019-13413-w
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