Mechanisms underlying endolysosomal deficits mediated by the Parkinson¿s disease-related kinase LRRK2
Year: 2019
Type: dissertation
Abstract: Mutations in the gene encoding for leucine-rich repeat kinase 2 (LRRK2) are a common cause of hereditary Parkinson´s disease (PD), and some variants also confer risk to develop sporadic PD. LRRK2 has been reported to regulate various intracellular vesicular trafficking pathways, including autophagy, retromer-mediated trafficking, synaptic vesicle dynamics and endolysosomal degradative events, although the precise molecular mechanism(s) underlying these alterations remain to be elucidated. \nRecent studies have revealed that a subset of Rab proteins involved in secretory and endocytic recycling are LRRK2 kinase substrates in vivo. However, the effects of LRRK2-mediated phosphorylation of these substrates on membrane trafficking remain unknown. Here, by studying the well-characterized epidermal growth factor receptor (EGFR) trafficking pathway, we report that expression of active or phospho-deficient, but not phospho-mimetic, RAB8A variants rescues the G2019S LRRK2-mediated effects on endolysosomal membrane trafficking. Similarly, upregulation of the RAB11-Rabin8-RAB8A cascade, which activates RAB8A, also reverted these trafficking deficits. Strikingly, we found that the loss of RAB8A delayed EGFR degradation and decreased RAB7A activity, mimicking the previously described effect of pathogenic LRRK2 on EGFR trafficking. \nMoreover, expression of pathogenic G2019S LRRK2 or loss of RAB8A resulted in mistargeting of the EGFR into a RAB4-positive endocytic compartment, which was accompanied not only by endocytic degradation defects, but also by a deficit in EGFR recycling to the plasma membrane. Both the accumulation of EGFR in the RAB4-positive compartment and the recycling deficits were rescued upon expression of active RAB7A. \nFinally, we showed that dominant-negative RAB7A expression resulted in similar defects in EGF degradation, accumulation in a RAB4 compartment, and deficits in EGFR recycling, which were all rescued upon expression of active RAB8A. \nTaken together, these findings suggest that LRRK2-mediated phosphorylation and subsequent impairment of RAB8A function may form the basis of how pathogenic LRRK2 deregulates endolysosomal transport and endocytic recycling events.
Author: Rivero Ríos, María del Pilar
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7058034524