Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload
Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload
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DOI：
10.1038/s41418-019-0442-2
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发表时间：
2020-05-01
影响因子：
12.4
通讯作者：
Duchen, Michael R.
中科院分区：
文献类型：
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作者：
Plotegher, Nicoletta;Perocheau, Dany;Duchen, Michael R.
溶酶体酶葡萄糖脑苷脂酶（GBA 1）的杂合突变代表帕金森病（PD）的主要遗传风险，而纯合GBA 1突变导致戈谢病，一种溶酶体储存障碍，可能涉及严重的神经变性。我们以前已经证明受损的自噬和蛋白酶体降解途径和线粒体功能障碍的神经元GBA 1基因敲除（gba 1（-/-））小鼠。我们现在表明，刺激与生理谷氨酸浓度导致病理[Ca 2 +]（c）的反应和延迟钙失调，线粒体膜电位的崩溃和ATP/ADP比例的不可逆下降。gba 1（-/-）细胞线粒体钙摄取减少，线粒体钙单向转运体的表达也减少。gba 1（-/-）神经元自由基产生率增加。gba 1（+/-）神经元的行为在所有变量方面与gba 1（-/-）相似，这与这些机制对PD发病机制的贡献一致。这些数据路标降低了生物能量能力和[Ca 2 +]（c）调节异常作为驱动神经退行性变的机制。
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.