Derailed degradation: LRRK2-dependent exocytosis in Parkinson’s disease

In this PNAS commentary, Shawn M. Ferguson discusses the implications of new data presented by Palumbos et al. regarding Parkinson's disease-associated gain-of-function LRRK2 mutations. These mutations are linked to a notable increase in neuronal exocytosis, specifically the release of extracellular vesicles. These vesicles are characterized by their enrichment in intraluminal endosomal components and, in the case of larger vesicles, a composition overlapping with neuronal autophagosomes. The commentary proposes two potential explanations for this phenomenon: a defect in the fusion of endosomes and autophagosomes with dysfunctional lysosomes, leading to their fusion with the plasma membrane, or a more direct role of LRRK2 in promoting lysosome exocytosis. The author highlights that the relationship between LRRK2 and exocytosis of lysosomes and lysosome-related organelles is a generalizable finding across various cell types. Mechanistically, LRRK2 is activated on stressed lysosomes via direct interaction with GABARAP, an ATG8 family member, through the CASM pathway, which is critical for lysosome exocytosis in macrophages. Interactions with Rab GTPases may also contribute to LRRK2 activity at endolysosomal organelles prior to exocytosis. The commentary also speculates on the pathophysiological relevance, particularly concerning the potential spread of pathogenic alpha-synuclein fibrils through exocytic release in Parkinson's disease. This work underscores the critical need for further research into LRRK2's role in lysosomal trafficking and quality control in neurons to understand Parkinson's disease and develop targeted therapies.