Leucine-Rich Repeat Kinase 2 Influences Fate Decision of Human Monocytes Differentiated from Induced Pluripotent Stem Cells

Abstract

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are strongly associated with familial Parkinson’s disease (PD). High expression levels in immune cells suggest a role of LRRK2 in regulating the immune system. In this study, we investigated the effect of the LRRK2 (G2019S) mutation in monocytes, using a human stem cell-derived model expressing LRRK2 at endogenous levels. We discovered alterations in the differentiation pattern of LRRK2 mutant, compared to non-mutant isogenic controls, leading to accelerated monocyte production and a reduction in the non-classical CD14+CD16+ monocyte subpopulation in the LRRK2 mutant cells. LPS-treatment of the iPSC-derived monocytes significantly increased the release of pro-inflammatory cytokines, demonstrating a functional response without revealing any significant differences between the genotypes. Assessment of the migrational capacity of the differentiated monocytes revealed moderate deficits in LRRK2 mutant cells, compared to their respective controls. Our findings indicate a pivotal role of LRRK2 in hematopoietic fate decision, endorsing the involvement of the immune system in the development of PD.

LRRK2 contributes to monocyte dysregulation in Parkinson’s disease

“…Our current observation that LRRK2 levels are elevated in monocytes of PD patients establishes a compelling link between a specific role of LRRK2 in immune cells and their contribution to PD pathogenesis. Together with the recent study by Speidel et al demonstrating a reduction in the non-classical CD14 + CD16 + monocyte subpopulation in PD LRRK2 mutant cells [25] our study forms strong evidence for the involvement of LRRK2 in PD monocyte dysregulation. Our current study also supports the idea that PD monocytes are in a pro-inflammatory predisposition as described earlier [11] and it might be that together with the co-occurrence of “second hits” like environmental cues or CNS factors triggering the peripheral immune system LRRK2 might be upregulated in monocytes.…”

LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson’s Disease Mouse Model

“… 40 Second, an increased LRRK2 protein level has been reported in PD brain regions with abundant LB pathology, in monocytes from PD cases, and in exosomes isolated from PD cases. 41 , 42 , 43 , 44 , 45 Third, in model systems, overexpression of either wild-type or PD-associated G2019S LRRK2 enhanced α-syn accumulation and downstream neuropathology in A53T α-syn mutant mice, and genetic ablation of LRRK2 not only reduced somatic α-syn accumulation but also significantly delayed A53T-induced neurodegeneration such as impaired microtubule dynamics and Golgi fragmentation. 46 , 47 Furthermore, genetic ablation of LRRK2 or treatment with a potent LRRK2 kinase inhibitor protected against DA cell loss caused by viral-mediated overexpression of α-syn.…”

Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

“…Stem Cells International migration ability of these monocytes was found to be impaired. These results indicate that LRRK2 also plays a key role in hematopoiesis, supporting the pathogenic role of immunity in PD [81].…”