Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.,Cell Death and Differentiation

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Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload.
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-11-04 , DOI: 10.1038/s41418-019-0442-2
Nicoletta Plotegher _{1,

2} , Dany Perocheau ₃ , Ruggero Ferrazza ₄ , Giulia Massaro ₅ , Gauri Bhosale ₁ , Federico Zambon ₁ , Ahad A Rahim ₅ , Graziano Guella ₄ , Simon N Waddington _{3,

6} , Gyorgy Szabadkai _{1,

7,

8} , Michael R Duchen ₁

Affiliation

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.

中文翻译：

GBA1 耗竭导致细胞生物能受损，使神经元对钙超载敏感。

溶酶体酶葡萄糖脑苷脂酶 (GBA1) 的杂合突变是帕金森病 (PD) 的主要遗传风险，而纯合 GBA1 突变会导致戈谢病（一种溶酶体贮积症），可能涉及严重的神经变性。我们之前已经证明 GBA1 敲除 (gba1-/-) 小鼠神经元的自噬和蛋白酶体降解途径受损以及线粒体功能障碍。我们现在表明，生理谷氨酸浓度的刺激会导致病理性 [Ca2+]c 反应并延迟钙失调、线粒体膜电位崩溃和 ATP/ADP 比率不可逆转的下降。 gba1-/- 细胞中线粒体 Ca2+ 摄取减少，线粒体钙单向转运蛋白的表达也减少。 gba1-/- 神经元中自由基的产生率增加。 gba1+/- 神经元的行为在所有变量方面与 gba1-/- 相似，与这些机制对 PD 发病机制的贡献一致。这些数据标志降低了生物能量能力和 [Ca2+]c 失调作为驱动神经退行性变的机制。

更新日期：2019-11-04

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