Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes

Parkinson’s disease-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene hyperactivate LRRK2 kinase activity and cause increased phosphorylation of Rab GTPases, important regulators of intracellular trafficking. We found that the most common LRRK2 mutation, LRRK2-G2019S, dramatically reduces the processivity of autophagosome transport in neurons in a kinase-dependent manner. This effect was consistent across an overexpression model, neurons from a G2019S knockin mouse, and human induced pluripotent stem cell (iPSC)-derived neurons gene edited to express the G2019S mutation, and the effect was reversed by genetic or pharmacological inhibition of LRRK2. Furthermore, LRRK2 hyperactivation induced by overexpression of Rab29, a known activator of LRRK2 kinase, disrupted autophagosome transport to a similar extent. Mechanistically, we found that hyperactive LRRK2 recruits the motor adaptor JNK-interacting protein 4 (JIP4) to the autophagosomal membrane, inducing abnormal activation of kinesin that we propose leads to an unproductive tug of war between anterograde and retrograde motors. Disruption of autophagosome transport correlated with a significant defect in autophagosome acidification, suggesting that the observed transport deficit impairs effective degradation of autophagosomal cargo in neurons. Our results robustly link increased LRRK2 kinase activity to defects in autophagosome transport and maturation, further implicating defective autophagy in the pathogenesis of Parkinson’s disease. [Display omitted] •Parkinson’s disease LRRK2-G2019S mutation disrupts axonal autophagosome transport•Rab29-induced LRRK2 hyperactivation also impairs autophagosome transport•Hyperactive LRRK2 recruits JIP4, causing a tug of war between autophagosome motors•Impaired axonal transport is accompanied by defective autophagosome acidification Boecker et al. find that hyperactivation of LRRK2 by a Parkinson’s disease-associated mutation disrupts the axonal transport of autophagosomes through the dysregulation of associated motors. Defective transport leads to impaired autophagosome maturation. Thus, dysfunctional autophagy is predicted to contribute to Parkinson’s disease pathogenesis.