AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression

Chengsong Xie,Hyun Jin Cho,Huaibin Cai

doi:10.1186/s40035-018-0106-z

Abstract

BackgroundLeucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death. RAGE, receptor of AGEs, is activated by interaction with AGEs and mediates AGE-induced cytotoxicity. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown.MethodsUsing cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type (WT) and G2019S transgenic mice, we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining. We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots.ResultsWe show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls. Furthermore, we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells.ConclusionsThese data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.

Highlights

Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD)
These data suggest that enhanced Advanced glycation end products (AGEs)-Receptor of AGEs (RAGE) interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD
After 15 days in vitro culture (15 DIV), the cultured striatal neurons were incubated with AGEs at the concentrations of 0.0125, 0.025, 0.05, 0.1, and 0.2 μg/μl for 24 h and the cells were immuno-stained with anti-MAP2 and anti-GFAP antibodies to count the surviving neurons and astrocytes, respectively (Fig 1b)

Summary

Introduction

Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD). LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown. Among PD-related causal genes, leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of sporadic and familial PD, as well as the late-onset PD [4]. The G2019S mutation has been identified as the most prevalent genetic cause of familial and sporadic PD [5]. It has been speculated that aging-related factors could contribute to G2019S LRRK2-linked PD pathogenesis

Methods

Results

Discussion

Conclusion