Figure 3.

Diagram of proposed mechanism(s) by which LRRK2 regulates autophagy via modulation of NAADP-dependent calcium channels (NAADP-R) on lysosomes. LRRK2 localizes to lysosomes and regulates calcium release through two-pore channels (TPCs). Whether this is due to a direct interaction of LRRK2 with NAADP-R, an indirect interaction via rab7 or additional proteins, or whether it is mediated by a phosphorylation event remains to be determined. Calcium release from acidic organelles then causes calcium-induced calcium release (CICR) from the ER to amplify cytosolic calcium signals, which leads to the activation of a cascade to increase autophagosome numbers. Diminished luminal calcium will further cause a decrease in autophagosome-lysosome fusion, and increased pH may have additional effects on eventually impairing lysosomal proteolysis, leading to the observed autophagic-lysosomal clearance phenotype.