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The unconventional G-protein cycle of LRRK2 and Roco proteins

Susanne Terheyden1, Laura M Nederveen-Schippers1, Arjan Kortholt1

  • 1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

Biochemical Society Transactions
|December 4, 2016
PubMed

Insights

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause hereditary Parkinson's disease. This review explores LRRK2's unusual G-protein cycle and activation mechanisms, crucial for understanding Parkinson's disease pathogenesis.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeat kinase 2 (LRRK2) mutations are the leading genetic cause of Parkinson's disease (PD).
  • LRRK2 is a member of the Roco protein family, featuring Roc, COR, and kinase domains.
  • The precise function and regulation of LRRK2, particularly in relation to PD-associated mutations, remain incompletely understood.

Purpose of the Study:

  • To review the current understanding of LRRK2's G-protein cycle.
  • To elucidate the intramolecular activation mechanisms of LRRK2.
  • To connect LRRK2's unique biochemical properties to Parkinson's disease pathogenesis.

Main Methods:

  • Review of recent biochemical and structural studies on LRRK2 and Roco proteins.
  • Analysis of LRRK2's noncanonical G-protein characteristics.
  • Integration of findings on LRRK2 activation with existing knowledge of PD genetics.

Main Results:

  • LRRK2 and related Roco proteins function as noncanonical G-proteins.
  • Activation of LRRK2 does not rely on classical guanine nucleotide exchange factors or GTPase-activating proteins.
  • Emerging evidence points to complex intramolecular mechanisms governing LRRK2 activity.

Conclusions:

  • LRRK2's distinct G-protein cycle offers novel insights into Parkinson's disease.
  • Understanding LRRK2's intramolecular activation is key to developing targeted therapies for hereditary PD.
  • Further research into LRRK2's unique biochemistry is essential for unraveling PD mechanisms.
Keywords:
G-proteins activated by nucleotide-dependent dimerization (GAD)Parkinson's diseaseRoco proteinsleucine-rich repeat kinase 2 (LRRK2)

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