G2019S mutation in the LRRK2 gene increases endosomal recruitment in iPSC-derived microglia

Abstract

Parkinson’s disease (PD) is an uncurable neurodegenerative disorder associated with progressive death of dopaminergic neurons and formation of Lewy’s Bodies, containing α-synuclein. Growing evidence suggests that PD progresses in a non-cell-autonomous manner, involving among others microglia, central nervous system macrophages. Genetic variation around the LRRK2 gene is associated with both familial and sporadic PD. In particular, the G2019S is the most common monogenic PD mutation. Although the cellular role of LRRK2 is only partially understood, an implication of the protein in the regulation of vesicle trafficking in the endolysosomal system has been highlighted. With this project we aim to elucidate LRRK2 role in the microglial endolysosomal system and whether an alteration of the system may lead to a rerouting of vesicle trafficking. Employing induced pluripotent stem cells, we generated microglia from a LRRK2 PD patient and its isogenic gene-corrected counterpart. Our findings highlight an impaired autophagy in LRRK2 PD iPSC-derived microglia and an increased recruitment of endosomes towards the lysosomes. In addition, we observed that in LRRK2 PD microglia a fraction of LE is addressed to the plasma membrane, probably for secretion. These results collectively suggest that G2019S mutation in LRRK2 gene in microglia may contribute to PD pathogenesis by impairing lysosomal degradation and increasing endosomal trafficking that may affect neuron survival.