Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation

Abstract

Parkinson disease-causing mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. We found that knockout of the LRRK2-counteracting RAB phosphatase PPM1H resulted in a gene dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in Parkinson disease pathophysiology. Defective autophagosome transport and impaired aSyn degradation also correlated with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that was dependent on LRRK2 kinase activity. Thus, our results link LRRK2-mediated RAB hyperphosphorylation to aSyn pathology in Parkinson disease and further establish a role for impaired autophagy in Parkinson disease pathophysiology.