LRRK2 I1371V Mutation Drives Astrocytic Glucose Metabolism Failure and Induces Integrated ER–Mitochondria–Lysosome Dysfunction in Parkinson’s Disease

Although LRRK2 mutations modulate systemic glucose homeostasis and metabolic dysfunction precedes Parkinson’s disease (PD) motor symptoms; the way in which pathogenic variants of LRRK2 disrupt astrocytic glucose metabolism and organellar homeostasis remains poorly understood. Here, we demonstrate that LRRK2-I1371V mutation causes profound metabolic and organellar dysfunction in LRRK2-I1371V PD-iPSC-derived astrocytes and U87 cells overexpressing I1371V variant. LRRK2-I1371V astrocytes exhibit significantly reduced GLUT1 expression and cell surface localization, resulting in impaired glucose uptake and decreased lactate production. This metabolic insufficiency correlates with cascading mitochondrial dysfunction, characterized by membrane depolarization, elevated reactive oxygen species, enhanced ubiquitination and reduced proteasomal activity. Reduced LAMP1/LAMP2 expression, impaired lysosomal acidification, and selective cathepsin D deficiency were observed. Accumulation of undegraded cargo was confirmed by transmission electron microscopy upon α-synuclein exposure. ER stress was evident by upregulation of GADD34/CHOP, increased phospho-PERK, and reduced nascent protein synthesis. Increased ER–mitochondrial contact via MAMs and enhanced STIM1-ORAI3 clustering reflect compensatory but ultimately insufficient responses to energy stress. Our results reveal that LRRK2-I1371V induces glucose uptake deficits, leading to energy depletion and integrated ER–mitochondria–lysosome dysfunction, thus indicating restoration of astrocytic metabolic capacity as a potential therapeutic strategy for LRRK2-associated PD.