Neurobiology: A pathogenic tug of war

Abstract

Pathogenic mutations in the kinase LRRK2 have been implicated in Parkinson's disease. A new study shows that hyperactivation of this kinase reduces the processivity of autophagosomal retrograde transport in axons through an unproductive 'tug-of-war' between anterograde and retrograde motors, thus contributing to autophagy dysfunction and axonal degeneration.

Figure 1.. A pathogenic tug-of-war model in PD-linked AV transport.

Axonal transport is driven by an integrated opposing force between the anterograde motor kinesin and the retrograde motor dynein. AVs are preferentially formed at the distal axonal tip and then undergo stepwise maturation along the dynein-driven trafficking pathway en route towards the soma for degradation. PD-linked hyperactive LRRK2 kinase reduces AV retrograde processivity and impairs their maturation through the phosphorylation of Rab proteins that recruit JIP4 to the outer membrane of AVs. JIP4 in turn recruits more kinesin motors that then engage with microtubules, thus leading to an unproductive tug-of-war. This model nicely interprets the striking phenotypes of the reduced AV processivity in LRRK2-G2019S neurons, where axonal AVs undergo more frequent pauses, spend more time in a paused status per AV, and display increased reversals.