A Link between Autophagy and the Pathophysiology of LRRK2 in Parkinson's Disease
Possible mechanisms by which LRRK2 may regulate events related to endolysosomal and autophagic function. Modulation of rab5 function could cause changes in endocytosis and/or autophagosome formation. Altered endocytosis could also modulate signalling events occurring at the plasma membrane or on intracellular organelles, thereby, indirectly impacting upon autophagy through phosphorylation events of distinct proteins required for the process. At later stages, through modulating rab7 function, LRRK2 may alter the fusion of autophagosomes/endosomes with lysosomes or impair lysosome reformation, which would impact upon autophagic-lysosomal clearance in both cases. As most of the abovementioned membrane fusion/reformation steps require intraluminal calcium, LRRK2 may further regulate endolysosomal clearance by modulating NAADP-sensitive calcium channels (NAADP-R) located on endosomes and lysosomes. The increasing intraluminal calcium concentrations along the endocytic/lysosomal pathway are indicated by the progressively darkened blue color. Ligand binding to receptors, followed by endocytosis and interaction with signalling complexes are schematically indicated. EE: early endosome; AV: autophagosome; LE/MVB: late endosome/multivesicular body; LYS: lysosome. For further details and references, see text.