Structural Biology of LRRK2 and its Interaction with Microtubules

Mov Disord. 2021 Nov;36(11):2494-2504. doi: 10.1002/mds.28755. Epub 2021 Aug 23.

Abstract

Mutations in leucine rich repeat kinase 2 (LRRK2) are a major cause of familial Parkinson's disease (PD) and a risk factor for its sporadic form. LRRK2 hyperactivity has also been reported in sporadic PD, making LRRK2 an appealing target for PD small-molecule therapeutics. At a cellular level, increasing evidence suggests that LRRK2 regulates membrane trafficking. Under some conditions LRRK2 also associates with microtubules, the cellular tracks used by dynein and kinesin motors to move membranes. At a structural level, however, relatively little was known about LRRK2. An important step toward bridging this gap took place last year with the publication of structures of LRRK2's cytosolic and microtubule-bound forms. Here, we review the main findings from these studies and discuss what we see as the major challenges going forward with a focus on areas that will require structural information. We also introduce the structural techniques-cryo-electron microscopy and cryo-electron tomography-that were instrumental to solving the structures of LRRK2. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: LRRK2; Parkinson's disease; cryo-EM; microtubules; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biology
  • Cryoelectron Microscopy
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Microtubules / chemistry
  • Mutation
  • Parkinson Disease* / genetics

Substances

  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2