Plotegher, N;
Perocheau, D;
Ferrazza, R;
Massaro, G;
Bhosale, G;
Zambon, F;
Rahim, AA;
... Duchen, MR; + view all
(2020)
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.
Cell Death & Differentiation
, 27
pp. 1588-1603.
10.1038/s41418-019-0442-2.
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Abstract
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} esponses 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.
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