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

Keywords

  • Rab proteins
  • Vesicle trafficking
  • GTPase
  • Phosphorylation

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