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Parkinson's disease-associated mutant LRRK2 phosphorylates Rab7L1 and modifies trans-Golgi morphology

Tetta Fujimoto1, Tomoki Kuwahara1, Tomoya Eguchi1

  • 1Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.

Biochemical and Biophysical Research Communications
|December 11, 2017
PubMed

Insights

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates Rab7L1, a protein linked to Parkinson's disease. This phosphorylation affects cellular processes and supports LRRK2's role in Parkinson's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in leucine-rich repeat kinase 2 (LRRK2) are a primary genetic cause of autosomal-dominant Parkinson's disease (PD).
  • LRRK2 influences intracellular trafficking and neurite outgrowth, with potential links to PD risk through interactors like Rab7L1.
  • Recent findings identify Rab GTPases as substrates for LRRK2 kinase activity.

Purpose of the Study:

  • To investigate the kinase activity of LRRK2 on Rab7L1 in cellular contexts.
  • To determine the specific phosphorylation site(s) on Rab7L1 targeted by LRRK2.
  • To elucidate the functional consequences of Rab7L1 phosphorylation by LRRK2 on cellular structures.

Main Methods:

  • In situ cellular assays including Phos-tag analysis and metabolic labeling.
  • In vitro kinase assays to confirm direct phosphorylation.
  • Site-directed mutagenesis of Rab7L1 (Ser/Thr to Alanine) and use of phospho-specific antibodies.

Main Results:

  • LRRK2 directly phosphorylates wild-type Rab7L1 at the Golgi, but not cytoplasmic mutant forms.
  • Serine 72 (Ser72) was identified as a major phosphorylation site on Rab7L1.
  • Pathogenic LRRK2 mutants significantly enhanced Ser72 phosphorylation of Rab7L1.
  • Modulation of Ser72 phosphorylation altered the morphology and distribution of the trans-Golgi network.

Conclusions:

  • Rab7L1 is a direct substrate of LRRK2, with Ser72 being a key phosphorylation site.
  • LRRK2-mediated phosphorylation of Rab7L1 influences the trans-Golgi network.
  • These findings support Rab7L1 phosphorylation as a mechanism in LRRK2-associated Parkinson's disease pathogenesis.
Keywords:
LRRK2Parkinson's diseasePhosphorylationRab7L1trans-Golgi

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