TY  - JOUR
AU  - Brunialti, Electra
AU  - Villa, Alessandro
AU  - Szego, Eva M
AU  - La Vitola, Pietro
AU  - Drago, Denise
AU  - Pavlovic, Radmila
AU  - Fontana, Laura
AU  - Tuna, Doga
AU  - Panzeri, Alessia
AU  - Meda, Clara
AU  - Weissleder, Christin
AU  - Rondinone, Ornella
AU  - Pitasi, Mattia
AU  - Miozzo, Monica
AU  - Deleidi, Michela
AU  - Andolfo, Annapaola
AU  - Di Monte, Donato A
AU  - Ciana, Paolo
TI  - Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models.
JO  - Journal of neuroinflammation
VL  - 22
IS  - 1
SN  - 1742-2094
CY  - London
PB  - BioMed Central
M1  - DZNE-2025-01314
SP  - 279
PY  - 2025
AB  - Mutations in the GBA gene, which reduce β-glucocerebrosidase (GCase) activity, represent the most significant genetic risk factor for Parkinson’s disease (PD). Decreased GCase activity has also been observed in sporadic PD cases, supporting a broader role for GCase in the poorly understood mechanisms underlying PD etiopathogenesis. While most studies on the relationship between GBA mutations and PD have focused on neurons, evidence suggests that PD pathology promoted by GCase deficiency involves other cell types and, in particular, interactions between neuronal and glial cells. Here, we identify microglia as primary players undergoing significant alterations at early stages of the pathological processes triggered by a GCase impairment. Using both pharmacological and genetic mouse models of GCase deficiency, we observed microglial morphological, transcriptional and metabolic changes. Interestingly, these changes were associated with a cell-specific, significant reduction of microglial ATP levels. When microglial ATP depletion was reproduced in an in vitro system of co-cultured microglial and neuronal cells, the neuroprotective properties of microglia were compromised, resulting in reduced cytoprotective and detoxifying pathways in neurons. These findings underscore the role of microglia in PD pathogenesis and point to a pathogenetic mechanism by which microglial metabolic disturbances leading to ATP depletion enhance neuronal vulnerability to injury and neurodegeneration. This mechanism could be targeted for therapeutic intervention aimed at mitigating PD risk and counteracting the development of PD pathology.The online version contains supplementary material available at 10.1186/s12974-025-03616-y.
KW  - ATP (Other)
KW  - Energetic failure (Other)
KW  - Gaucher’s disease (Other)
KW  - Microglia (Other)
KW  - Neuroprotection (Other)
KW  - Parkinson’s disease (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41291747
C2  - pmc:PMC12648879
DO  - DOI:10.1186/s12974-025-03616-y
UR  - https://pub.dzne.de/record/282551
ER  -