Mutations in the leucine-rich repeat kinase 2 (LRRK2) that increase kinase activity are associated with some forms of Parkinson's disease (PD). While increased LRRK2 activity is linked to impaired lysosomal function, the underlying molecular mechanisms are incompletely understood.

Using mutant mouse models and human induced pluripotent stem cell–derived macrophages and microglia, the authors show an inverse correlation between LRRK2 activity and the mRNA levels of lysosomal hydrolases and cathepsins responsible for lysosomal proteolytic activity. Notably, the abundance and nuclear translocation of the transcription factor TFE3, one of the master lysosomal gene expression regulators, was found to be inhibited by LRRK2.

This study reveals a new player that links LRRK2 to lysosomal function and positions the TFE family as a potentially promising target in the pathogenesis of PD.

This preprint has been assigned the following badges: New Hypothesis, Cross-Species, New Materials, Cross-Validation.

Read the preprint on bioRxiv (Yadavalli and Ferguson, 2022): https://doi.org/10.1101/2022.12.17.520834.