The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human

Rafeeq Mir, Francesca Tonelli, Pawel Lis, Thomas Macartney, Nicole K. Polinski, Terina N. Martinez, Meng-Yun Chou, Andrew Howden, Theresa König, Christoph Hotzy, Ivan Milenkovic, Thomas Brücke, Alexander Zimprich, Esther Sammler (Lead / Corresponding author), Dario Alessi (Lead / Corresponding author)

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Abstract

Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson’s disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (lung, kidney, spleen and brain). Furthermore, LRRK2 mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson’s patients with a heterozygous VPS35[D620N] mutation compared to healthy donors and idiopathic Parkinson’s patients. LRRK2 mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild type, LRRK2[R1441C] or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson’s patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing Parkinson’s disease through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson’s might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans.
Original languageEnglish
Pages (from-to)1861-1883
Number of pages19
JournalBiochemical Journal
Volume475
Issue number11
Early online date9 May 2018
DOIs
Publication statusPublished - 6 Jun 2018

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Phosphorylation
Parkinson Disease
Mutation
Proteins
Phosphotransferases
Genes
Fibroblasts
Brain
Tissue
Missense Mutation
Monocytes
Neutrophils
Spleen
Tissue Donors
Clinical Trials
Kidney
Lung

Keywords

  • Rab proteins
  • Vesicle trafficking
  • GTPase
  • Phosphorylation

Cite this

Mir, Rafeeq ; Tonelli, Francesca ; Lis, Pawel ; Macartney, Thomas ; Polinski, Nicole K. ; Martinez, Terina N. ; Chou, Meng-Yun ; Howden, Andrew ; König, Theresa ; Hotzy, Christoph ; Milenkovic, Ivan ; Brücke, Thomas ; Zimprich, Alexander ; Sammler, Esther ; Alessi, Dario. / The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human. In: Biochemical Journal. 2018 ; Vol. 475, No. 11. pp. 1861-1883.
@article{334817bf376c43f2ad8e7d3c3d9c33c0,
title = "The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human",
abstract = "Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson’s disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (lung, kidney, spleen and brain). Furthermore, LRRK2 mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson’s patients with a heterozygous VPS35[D620N] mutation compared to healthy donors and idiopathic Parkinson’s patients. LRRK2 mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild type, LRRK2[R1441C] or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson’s patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing Parkinson’s disease through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson’s might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans.",
keywords = "Rab proteins, Vesicle trafficking, GTPase, Phosphorylation",
author = "Rafeeq Mir and Francesca Tonelli and Pawel Lis and Thomas Macartney and Polinski, {Nicole K.} and Martinez, {Terina N.} and Meng-Yun Chou and Andrew Howden and Theresa K{\"o}nig and Christoph Hotzy and Ivan Milenkovic and Thomas Br{\"u}cke and Alexander Zimprich and Esther Sammler and Dario Alessi",
note = "This work was supported by the Michael J. Fox Foundation for Parkinson's research [grant number 6986 (to D.R.A.)]; the Medical Research Council [grant number MC_UU_12016/2 (to D.R.A.)]; the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (BoehringerIngelheim, GlaxoSmithKline, and Merck KGaA, to D.R.A.). E.S is supported by an Academic Health Sciences Partnership in Tayside (AHSP) Clinical Fellowship.",
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language = "English",
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Mir, R, Tonelli, F, Lis, P, Macartney, T, Polinski, NK, Martinez, TN, Chou, M-Y, Howden, A, König, T, Hotzy, C, Milenkovic, I, Brücke, T, Zimprich, A, Sammler, E & Alessi, D 2018, 'The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human', Biochemical Journal, vol. 475, no. 11, pp. 1861-1883. https://doi.org/10.1042/BCJ20180248

The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human. / Mir, Rafeeq; Tonelli, Francesca; Lis, Pawel; Macartney, Thomas; Polinski, Nicole K.; Martinez, Terina N.; Chou, Meng-Yun ; Howden, Andrew; König, Theresa ; Hotzy, Christoph ; Milenkovic, Ivan ; Brücke, Thomas ; Zimprich, Alexander ; Sammler, Esther (Lead / Corresponding author); Alessi, Dario (Lead / Corresponding author).

In: Biochemical Journal, Vol. 475, No. 11, 06.06.2018, p. 1861-1883.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Parkinson's disease VPS35[D620N] mutation enhances LRRK2 mediated Rab protein phosphorylation in mouse and human

AU - Mir, Rafeeq

AU - Tonelli, Francesca

AU - Lis, Pawel

AU - Macartney, Thomas

AU - Polinski, Nicole K.

AU - Martinez, Terina N.

AU - Chou, Meng-Yun

AU - Howden, Andrew

AU - König, Theresa

AU - Hotzy, Christoph

AU - Milenkovic, Ivan

AU - Brücke, Thomas

AU - Zimprich, Alexander

AU - Sammler, Esther

AU - Alessi, Dario

N1 - This work was supported by the Michael J. Fox Foundation for Parkinson's research [grant number 6986 (to D.R.A.)]; the Medical Research Council [grant number MC_UU_12016/2 (to D.R.A.)]; the pharmaceutical companies supporting the Division of Signal Transduction Therapy Unit (BoehringerIngelheim, GlaxoSmithKline, and Merck KGaA, to D.R.A.). E.S is supported by an Academic Health Sciences Partnership in Tayside (AHSP) Clinical Fellowship.

PY - 2018/6/6

Y1 - 2018/6/6

N2 - Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson’s disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (lung, kidney, spleen and brain). Furthermore, LRRK2 mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson’s patients with a heterozygous VPS35[D620N] mutation compared to healthy donors and idiopathic Parkinson’s patients. LRRK2 mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild type, LRRK2[R1441C] or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson’s patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing Parkinson’s disease through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson’s might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans.

AB - Missense mutations in the LRRK2 and VPS35 genes result in autosomal dominant Parkinson’s disease. The VPS35 gene encodes for the cargo-binding component of the retromer complex, while LRRK2 modulates vesicular trafficking by phosphorylating a subgroup of Rab proteins. Pathogenic mutations in LRRK2 increase its kinase activity. It is not known how the only thus far described pathogenic VPS35 mutation, [D620N] exerts its effects. We reveal that the VPS35[D620N] knock-in mutation, strikingly elevates LRRK2 mediated phosphorylation of Rab8A, Rab10 and Rab12 in mouse embryonic fibroblasts. The VPS35[D620N] mutation also increases Rab10 phosphorylation in mouse tissues (lung, kidney, spleen and brain). Furthermore, LRRK2 mediated Rab10 phosphorylation is increased in neutrophils as well as monocytes isolated from three Parkinson’s patients with a heterozygous VPS35[D620N] mutation compared to healthy donors and idiopathic Parkinson’s patients. LRRK2 mediated Rab10 phosphorylation is significantly suppressed by knock-out or knock-down of VPS35 in wild type, LRRK2[R1441C] or VPS35[D620N] cells. Finally, VPS35[D620N] mutation promotes Rab10 phosphorylation more potently than LRRK2 pathogenic mutations. Available data suggest that Parkinson’s patients with VPS35[D620N] develop the disease at a younger age than those with LRRK2 mutations. Our observations indicate that VPS35 controls LRRK2 activity and that the VPS35[D620N] mutation results in a gain of function, potentially causing Parkinson’s disease through hyperactivation of the LRRK2 kinase. Our findings suggest that it may be possible to elaborate compounds that target the retromer complex to suppress LRRK2 activity. Moreover, patients with VPS35[D620N] associated Parkinson’s might benefit from LRRK2 inhibitor treatment that have entered clinical trials in humans.

KW - Rab proteins

KW - Vesicle trafficking

KW - GTPase

KW - Phosphorylation

U2 - 10.1042/BCJ20180248

DO - 10.1042/BCJ20180248

M3 - Article

C2 - 29743203

VL - 475

SP - 1861

EP - 1883

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

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