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Hyperactive LRRK2 kinase impairs the trafficking of axonal autophagosomes

C Alexander Boecker1, Erika L F Holzbaur1

  • 1Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Autophagy
|June 10, 2021
PubMed

Insights

Parkinson disease mutations in LRRK2 (leucine rich repeat kinase 2) cause kinase hyperactivation, disrupting axonal transport of autophagosomes in neurons. This defect impairs autophagosome maturation, highlighting a role for faulty autophagy in Parkinson disease pathogenesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of Parkinson disease (PD).
  • LRRK2 mutations lead to increased kinase activity, but the precise mechanisms linking this to PD pathogenesis remain under investigation.
  • Autophagy, a cellular degradation process, is implicated in neurodegenerative diseases like PD.

Purpose of the Study:

  • To investigate the impact of LRRK2 hyperactivation on axonal autophagosome transport in neurons.
  • To elucidate the molecular mechanisms by which LRRK2 mutations disrupt autophagosome trafficking.
  • To establish the role of impaired autophagosome transport and maturation in LRRK2-associated PD.

Main Methods:

  • Utilized three distinct cellular and animal models expressing the common PD-associated LRRK2 G2019S mutation.
  • Assessed autophagosome transport dynamics in neurons using advanced microscopy techniques.
  • Investigated the interaction between LRRK2, SPAG9/JIP4, and motor proteins (kinesin-1) using biochemical and cellular assays.

Main Results:

  • Expression of LRRK2 G2019S significantly disrupted processive autophagosome transport in an LRRK2 kinase-dependent manner.
  • Hyperactive LRRK2 was found to recruit SPAG9/JIP4 to the autophagosomal membrane, leading to aberrant kinesin-1 activity.
  • This aberrant motor activity resulted in a motor protein "tug-of-war," impairing autophagosome movement and maturation.
  • Defective autophagosome transport correlated with impaired cargo degradation, suggesting a link to neurodegeneration.

Conclusions:

  • LRRK2 kinase hyperactivation is sufficient to cause defects in axonal autophagosome transport and maturation.
  • The recruitment of SPAG9/JIP4 by hyperactive LRRK2 plays a critical role in disrupting motor protein function and autophagosome trafficking.
  • These findings provide strong evidence for a role of impaired autophagy and defective axonal transport in the pathogenesis of Parkinson disease.
Keywords:
AutophagyJIP4LRRK2Parkinson’s diseaseaxonal transport

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