Impaired Cellular Bioenergetics Caused by GBA1 Depletion Sensitizes Neurons to Calcium Overload

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2019 Nov 6

PMID 31685979

Citations 15

Authors

Nicoletta Plotegher

Dany Perocheau

Ruggero Ferrazza

Giulia Massaro

Gauri Bhosale

Federico Zambon

Ahad A Rahim

Graziano Guella

Simon N Waddington

Gyorgy Szabadkai

Michael R Duchen

Affiliations

Soon will be listed here.

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

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