Association of LAG3 genetic variation with an increased risk of PD in Chinese female population

Abstract

BackgroundEmerging evidence suggests that α-synuclein (α-syn) aggregation and intercellular transmission contributes to pathogenesis of Parkinson’s disease (PD) and the toxic fibrillary α-syn binds lymphocyte-activation gene 3 (LAG3) receptor that mediates α-syn transmission. The deletion of LAG3 in animal models was shown to limit α-syn spreading and alleviate the pathological changes of dopaminergic neurons and animal behavioral deficits induced by α-syn aggregation. However, little is known about the genetic association of LAG3 variation with human PD development.ObjectiveHere we investigated LAG3 single nucleotide polymorphisms (SNPs) and examined the levels of soluble LAG3 (sLAG3) of CSF and serum from Chinese PD patients.MethodsWe enrolled 646 PD patients and 536 healthy controls to conduct a case-control study. All the participants were genotyped using Sequenom iPLEX Assay and the partial cerebrospinal fluid (CSF) and serum samples were assessed by Meso Scale Discovery electrochemiluminescence (MSD-ECL) immunoassay to measure sLAG3 concentration.ResultsAs a result, distributions of rs1922452-AA (1.975, 95% confidence interval (CI) 1.311–2.888, p = 0.001) and rs951818-CC (OR = 2.03, 95% CI 1.369–3.010, p = 0.001) genotype frequencies were found higher in the female PD patients than controls, respectively, and a strong linkage disequilibrium (LD) was calculated on the variants. The level of sLAG3 in CSF of PD patients was found to significantly differ from that of controls (51.56 ± 15.05 pg/ml vs 88.49 ± 62.96 pg/ml, p < 0.0001). Meanwhile, the concentration of α-synuclein in CSF of patients was significantly lower than that of controls (939.9 ± 2900 pg/ml vs 2476 ± 4403 pg/ml, p < 0.0001) and the level of sLAG3 was detected to be positive correlation with that of α-synuclein in the control group (r = 0.597, p = 0.0042), but not in PD group (r = 0.111, p = 0.408).ConclusionIn summary, our data suggested that LAG3 SNPs increase the PD risk of Chinese female population and the sLAG3 may be a potential biomarker predicted for PD development.

Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

“…Gender, age, disease duration and severity as assessed by Hoehn and Yahr PD staging, did not significantly affect sLAG3 concentration in CSF of PD patients [40]. The estimated sensitivity and specificity of CSF sLAG3 as a possible PD biomarker were about 45% and 90%, respectively [40]. Although the sensitivity is low, this is the result of a single study applying MSD-ECL in CSF samples, where concentration of the antigen may be low or the affinity reagents may need better standardization.…”

“…Although the sensitivity is low, this is the result of a single study applying MSD-ECL in CSF samples, where concentration of the antigen may be low or the affinity reagents may need better standardization. However, the high estimated specificity of CSF sLAG3 is very encouraging [40].…”

“…Indeed, the MSD-ECL technology displays higher repeatability, stability, sensitivity and homogeneity than ELISA assay [41]. Gender, age, disease duration and severity as assessed by Hoehn and Yahr PD staging, did not significantly affect sLAG3 concentration in CSF of PD patients [40]. The estimated sensitivity and specificity of CSF sLAG3 as a possible PD biomarker were about 45% and 90%, respectively [40].…”

“…Based on these interesting evidences, another larger study aimed to additionally explore the potential role of sLAG3 in the CSF as a potential PD biomarker in a Chinese cohort [40]. More specifically, it was demonstrated that the mean sLAG3 levels in CSF were lower in PD cases compared to healthy controls, whereas no significant differences were observed in the case of serum sLAG3 levels between these groups [40]. These results are in disagreement with the findings of the previously mentioned study, in which serum sLAG3 levels were increased in PD patients compared to controls.…”

Potent inhibitors of toxic alpha-synuclein oligomers identified via cellular time-resolved FRET biosensor

“…Lewy bodies are a shared, fibrillar, pathological hallmark of many alpha-synucleinopathies. These fibrillar inclusion have been posited to be contain neurotoxic species with a direct link to the prion-like, cell-to-cell spread of pathology throughout the central nervous system 31,[42][43][44][45][46][47] . Indeed, numerous rodent models have been developed using intramuscular or intra-striatal injection of sonicated pre-formed fibrils (PFF) and produce robust and temporally staged PD-like pathology 44,[48][49][50][51][52][53] .…”