Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

LRRK2-G2019S Synergizes with Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation that Precede Nigrostriatal Degeneration

“…With regard to microglia, both in vitro and in vivo studies show that LRRK2 modulate microglia inflammatory responses. 53,55,56,[151][152][153] Recent studies suggest that LRRK2 levels in microglia may not have a direct effect on neuroinflammation in PD, as in vivo injection of a high acute dose of LPS failed to increase microglia LRRK2 protein levels in R1441C and G2019S young adult mice 70 . Similar results have been observed ex vivo, with neither LPS 154 or priming with a-syn pre-formed fibrils 155 increasing LRRK2 protein expression in cultured murine microglia.…”

LRRK2-G2019S Synergizes With Ageing and Low-Grade Inflammation to Promote Gut and Peripheral Immune Cell Activation That Precede Nigrostriatal Degeneration

“…150 With regard to microglia, both in vitro and in vivo studies show that LRRK2 modulate microglia inflammatory responses. 53,55,56,[151][152][153] Recent studies suggest that LRRK2 levels in microglia may not have a direct effect on neuroinflammation in PD, as in vivo injection of a high acute dose of LPS failed to increase microglia LRRK2 protein levels in R1441C and G2019S young adult mice 70 . Similar results have been observed ex vivo, with neither LPS 154 or priming with a-syn pre-formed fibrils 155 increasing LRRK2 protein expression in cultured murine microglia.…”

The Mechanism and Function of Glia in Parkinson's Disease

“…Lin and their colleagues found that DJ-1 regulated microglial activation in response to lipopolysaccharide (LPS) treatment. DJ-1 deficiency in microglia increases the neurotoxicity induced by LPS (Mamais et al, 2021).…”