Metabolic reprogramming and ATP imbalance weaken microglial neuroprotection in β-glucocerebrosidase deficiency

Mutations in the GBA gene, which result in reduced activity of the lysosomal enzyme β-glucocerebrosidase (GCase), constitute the strongest known genetic risk factor for Parkinson’s disease (PD). Importantly, diminished GCase activity has also been reported in sporadic forms of PD, suggesting that alterations in GCase function contribute more broadly to the poorly understood molecular and cellular mechanisms underlying PD etiopathogenesis. While most research investigating the relationship between GBA mutations and PD has predominantly focused on neuronal dysfunction and α-synuclein pathology, emerging evidence indicates that GCase deficiency drives pathological changes in other brain cells. In particular, the cross-talk between neurons and glial cells appears to play a central role in shaping disease progression. Here, we identify microglia as critical players that undergo profound and early alterations following GCase impairment. By employing both pharmacological inhibition and genetic mouse models of GCase deficiency, we observed that microglia display substantial morphological remodeling, transcriptional reprogramming, and metabolic disturbances. Remarkably, these changes were consistently associated with a cell type–specific and significant reduction in microglial ATP levels, pointing to an energy imbalance as a central event in the pathological cascade. To directly assess the functional consequences of this metabolic disruption, we experimentally reproduced microglial ATP depletion in an in vitro co-culture system of microglia and neurons. Under these conditions, microglia exhibited a marked loss of their neuroprotective properties, which in turn rendered neurons more vulnerable to oxidative stress–induced damage. These results establish a direct mechanistic link between microglial metabolic dysfunction and increased neuronal susceptibility, thereby identifying microglial bioenergetic failure as a key driver of neurodegeneration in the context of GCase deficiency. Taken together, our findings not only reinforce the importance of microglia in PD pathogenesis but also reveal a possible pathogenetic mechanism whereby disturbances in microglial metabolism and ATP homeostasis amplify neuronal vulnerability and injury. This mechanistic insight highlights microglia as a promising therapeutic target, suggesting that interventions aimed at restoring microglial metabolic balance and preserving ATP availability could help mitigate PD risk and potentially counteract the progression of PD pathology.