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Publication Detail
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Plotegher N, Perocheau D, Ferrazza R, Massaro G, Bhosale G, Zambon F, Rahim AA, Guella G, Waddington SN, Szabadkai G, Duchen MR
  • Publication date:
  • Journal:
    Cell Death Differ
  • Status:
    Published online
  • Country:
  • PII:
  • Language:
Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson's disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1-/-) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca2+]c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca2+ uptake was reduced in gba1-/- cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1-/- neurons. Behavior of gba1+/- neurons was similar to gba1-/- in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca2+]c dysregulation as mechanisms driving neurodegeneration.
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