| First Author | Plotegher N | Year | 2020 |
| Journal | Cell Death Differ | Volume | 27 |
| Issue | 5 | Pages | 1588-1603 |
| PubMed ID | 31685979 | Mgi Jnum | J:302822 |
| Mgi Id | MGI:6510114 | Doi | 10.1038/s41418-019-0442-2 |
| Citation | Plotegher N, et al. (2020) Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload. Cell Death Differ 27(5):1588-1603 |
| abstractText | 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. |
