Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload
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Nicoletta Plotegher Dany Perocheau Ruggero Ferrazza Giulia Massaro Gauri Bhosale Federico Zambon Ahad A Rahim Graziano Guella Simon N Waddington Gyorgy Szabadkai Michael R DuchenAbstract
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.
Journal details
Journal Cell Death and Differentiation
Volume 27
Issue number 5
Pages 1588-1603
Available online
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Publisher website (DOI) 10.1038/s41418-019-0442-2
Europe PubMed Central 31685979
Pubmed 31685979
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