Explore the intricacies of Parkinson's disease through this 25-minute multimedia lecture titled "Leucine-rich repeat kinase 2 (LRRK2)" by Prof. Mark Cookson, available in HS Talks under the Biomedical & Life Sciences Collection. The lecture covers critical milestones from 2002, unveiling a new locus, to familial variants in 2004-2005, and a common variant in 2005. The spotlight then shifts to LRRK2 domains and mutations, spotlighting the impact of ROC: COR mutations and the heightened kinase activity induced by LRRK2 p.G2019S. The lecture sheds light on the significance of LRRK2's role in regulating a subset of Rab GTPases and how multiple mutations enhance its kinase activity, raising the pivotal question: is this kinase activity crucial for pathogenesis? Professor Cookson's insights extend to in vivo experiments with kinase inhibitors and a summary of data gleaned from Genome-Wide Association Studies (GWAS), with a focus on two signals, variable penetrance, and a pleomorphic risk locus. The lecture also unravels the intricate relationship between LRRK2 and endolysosomes through experiments in knock-out mice, lysosomal inhibitors, and the intriguing phenomenon of lysosomal tubulation/sorting driven by LRRK2 (LYTL). The journey continues with discussions on LRRK2 activation pathways, its presence in immune cells, and a parallel mechanism in neurons. Prof. Cookson integrates genetic and functional perspectives, exploring single-cell brain expression by genotype and LRRK2 activity in the human frontal cortex and microglia, with a poignant note on the age-related increase of LRRK2 in microglia. The lecture concludes by highlighting the value of single-cell validation in iPSC-derived cells, a screen for functional variants, and the intricate interplay between inflammation and lysosomal gene expression.For further details, watch a video