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@ARTICLE{Brunialti:282551,
      author       = {Brunialti, Electra and Villa, Alessandro and Szego, Eva M
                      and La Vitola, Pietro and Drago, Denise and Pavlovic,
                      Radmila and Fontana, Laura and Tuna, Doga and Panzeri,
                      Alessia and Meda, Clara and Weissleder, Christin and
                      Rondinone, Ornella and Pitasi, Mattia and Miozzo, Monica and
                      Deleidi, Michela and Andolfo, Annapaola and Di Monte, Donato
                      A and Ciana, Paolo},
      title        = {{M}etabolic reprogramming and altered {ATP} content impair
                      neuroprotective functions of microglia in
                      β-glucocerebrosidase deficiency models.},
      journal      = {Journal of neuroinflammation},
      volume       = {22},
      number       = {1},
      issn         = {1742-2094},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2025-01314},
      pages        = {279},
      year         = {2025},
      abstract     = {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.},
      keywords     = {ATP (Other) / Energetic failure (Other) / Gaucher’s
                      disease (Other) / Microglia (Other) / Neuroprotection
                      (Other) / Parkinson’s disease (Other)},
      cin          = {AG Di Monte},
      ddc          = {610},
      cid          = {I:(DE-2719)1013008},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41291747},
      pmc          = {pmc:PMC12648879},
      doi          = {10.1186/s12974-025-03616-y},
      url          = {https://pub.dzne.de/record/282551},
}