2026 American Academy of Neurology Abstract Website

Objective:

To investigate the role of leucine-rich repeat kinase 2 (LRRK2) in glioblastoma (GBM) biology.

Background:

GBM is an aggressive brain tumor with limited treatment options. While LRRK2 gain-of-function variants are linked to autosomal-dominant Parkinson’s disease, emerging evidence suggests a potential tumor-suppressive role in GBM. Prior studies suggest that elevated LRRK2 expression may be associated with improved outcomes in GBM, particularly in TP53 wild-type tumors.

Design/Methods:

In silico analyses were performed using GlioVis, the Chinese Glioma Genome Atlas (CGGA), cBioPortal, and the Human Protein Atlas (HPA). LRRK2 mRNA and protein expression were examined in relation to overall survival (OS) and key GBM prognostic markers (MGMT, TP53, ATRX, CDKN2A/B). Subgroup analyses were performed across transcriptional subtypes (classical, mesenchymal, proneural).

Results:

LRRK2 mRNA expression trended lower in GBM versus non-tumor tissue (GlioVis: p = 0.40). Higher LRRK2 mRNA levels correlated with non-significant OS improvement in primary GBM (GlioVis: HR = 1.19, p = 0.33; CGGA: p = 0.08; cBioPortal: HR = 0.93, p = 0.83), but with significantly improved OS in recurrent GBM (CGGA: p = 0.047). Elevated LRRK2 protein expression was associated with improved OS (HPA: p = 0.034). LRRK2 mRNA expression negatively correlated with TP53 (GlioVis: r = -0.30, p<0.001), CDKN2A (CGGA: r = -0.272, p<0.001), and CDKN2B (CGGA: r = -0.15, p = 0.05), while positively correlated with IDH1 (CGGA: r = 0.291, p<0.001) and ATRX (CGGA: r = 0.231, p = 0.03). Subtype analyses showed persistent negative correlations with TP53, CDKN2A/B, and MGMT in classical and mesenchymal GBM.

Conclusions:

Elevated LRRK2 expression, particularly in recurrent GBM, is associated with improved OS, supporting LRRK2’s potential tumor-suppressive role. The variable correlations across GBM transcriptional subtypes suggest complex, subtype-dependent function for LRRK2, warranting further investigation.