Objective: This study explores how non-neuronal dysfunction drives the rapid progression of GBA-PD, aiming to identify therapeutic targets that restore protein degradation and cellular stability.

Background: Parkinson’s disease (PD) associated with GBA1 mutations (GBA-PD) is the most common genetic risk factor for the condition, characterized by reduced β-glucocerebrosidase activity and alpha-synuclein accumulation. This disrupts cellular homeostasis by impairing lysosomal function and autophagy, which are crucial for protein clearance. It is becoming more evident that GBA-PD involves systemic cellular failure in addition to neuronal loss. Consequently, investigating the interplay between different cell types is vital to fully map the multi-systemic nature of the disease.

Method: Monocytes isolated from GBA-PD patients, non-manifesting carriers, and healthy controls were differentiated into macrophages and fed with heat-killed HAP-1 GBA-KO cells to simulate the phagocytosis of GBA-deficient cellular debris. Subsequently, cells were exposed to lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to induce a robust inflammatory response through the activation and release of the inflammasome. Four experimental conditions were established to analyze the combined impact of substrate accumulation, phagocytic workload, and cellular stress on the GBA-PD phenotype.

Results: GBA-PD cells exhibited marked alterations in lysosomal and autophagic markers, reflecting an impaired response to the combined burden of enzymatic deficiency and phagocytic activity. Instead of maintaining equilibrium, these cells showed signs of persistent cellular stress and a reduced capacity to process internalized material. According to our data, GBA-deficient cells function at a metabolic exhaustion threshold where further stimuli impair their capacity to control degradative pathways and preserve intracellular stability.

Conclusion: These preliminary findings highlight how GBA deficiency alters the fundamental mechanisms of lysosomal-autophagic adaptation, leading to cellular stress and possibly an inefficient immune response. Such cellular insights are crucial for understanding the systemic drivers of neurodegeneration and for developing strategies aimed at mitigating the metabolic strain associated with GBA1 mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/impact-of-alpha-synuclein-burden-and-cellular-stress-on-gba-pd-macrophage/