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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 [Ca 2+ ] c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca 2+ 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 [Ca 2+ ] c dysregulation as mechanisms driving neurodegeneration.

Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload