Hyperactive LRRK2 kinase impairs the trafficking of axonal autophagosomes

Parkinson disease (PD)-causing mutations in the LRRK2 (leucine rich repeat kinase 2) gene hyperactivate LRRK2 kinase activity. Here, we discuss our recent work linking LRRK2 hyperactivation to defective axonal autophagosome transport in neurons. In three different models, we observed that expression of the most common causative mutation for PD, LRRK2(G2019S), disrupts processive autophagosome transport in a kinase-dependent manner. Mechanistically, we found that hyperactive LRRK2 recruits SPAG9/JIP4, a motor adaptor known to bind to LRRK2-phosphorylated RAB proteins, to the autophagosomal membrane. Increased SPAG9/JIP4 levels induce abnormal recruitment and activation of kinesin-1, which we propose results in an unproductive tug-of-war between anterograde and retrograde motors bound to autophagosomes. Disruption of autophagosome transport correlates with defective autophagosome maturation, suggesting that hyperactive LRRK2 may impair efficient degradation of autophagosomal cargo. Our work demonstrates that LRRK2 hyperactivation is sufficient to induce defects in autophagosome transport and maturation, further establishing a role of defective autophagy in the pathogenesis of PD.

Automated summary

The hyperactivation of LRRK2 kinase activity is linked to defective axonal autophagosome transport in neurons, particularly in the context of Parkinson's disease. This disruption is caused by the recruitment of SPAG9/JIP4 and subsequent abnormal activation of kinesin-1, leading to impaired autophagosome maturation and degradation. Overall, these findings further establish the significance of defective autophagy in the pathogenesis of PD.