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.

Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload / Plotegher, N.; Perocheau, D.; Ferrazza, R.; Massaro, G.; Bhosale, G.; Zambon, F.; Rahim, A. A.; Guella, G.; Waddington, S. N.; Szabadkai, G.; Duchen, M. R.. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - STAMPA. - 27:5(2020), pp. 1588-1603. [10.1038/s41418-019-0442-2]

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

Ferrazza R.;Guella G.;
2020-01-01

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 [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.
2020
5
Plotegher, N.; Perocheau, D.; Ferrazza, R.; Massaro, G.; Bhosale, G.; Zambon, F.; Rahim, A. A.; Guella, G.; Waddington, S. N.; Szabadkai, G.; Duchen, M. R.
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload / Plotegher, N.; Perocheau, D.; Ferrazza, R.; Massaro, G.; Bhosale, G.; Zambon, F.; Rahim, A. A.; Guella, G.; Waddington, S. N.; Szabadkai, G.; Duchen, M. R.. - In: CELL DEATH AND DIFFERENTIATION. - ISSN 1350-9047. - STAMPA. - 27:5(2020), pp. 1588-1603. [10.1038/s41418-019-0442-2]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/270652
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