The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis.
The distribution and function of GDE2, a regulator of spinal motor neuron survival, are disrupted in Amyotrophic Lateral Sclerosis.
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DOI：
10.1186/s40478-022-01376-x
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发表时间：
2022-05-12
影响因子：
7.1
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中科院分区：
文献类型：
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肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，影响上、下运动神经元的活力。目前的治疗选择是有限的，需要更深入地了解ALS发病机制。甘油磷酸二酯磷酸二酯酶2 （GDE2或GDPD5）是一种六跨膜蛋白，作用于细胞表面裂解糖基磷脂酰肌醇（GPI）锚点，将一些蛋白质拴在膜上。GDE2是脊髓运动神经元存活所必需的，但GDE2的神经保护活性是否在ALS中被破坏尚不清楚。我们利用小鼠模型和患者死后样本的组合来评估ALS中GDE2的功能。在SOD1G93A小鼠中，GDE2的单倍遗传减少加重了运动神经元的变性和丧失，而在SOD1WT转基因动物中则没有，这表明SOD1G93A环境下GDE2的神经保护功能减弱。在ALS患者的组织样本中，GDE2蛋白的总水平与健康对照组相当；然而，GDE2的膜水平显著降低。事实上，GDE2被发现异常地积聚在ALS运动皮层的细胞内区室中，这与细胞表面GDE2功能的破坏相一致。串联质量标签质谱法显示，与对照组相比，ALS患者释放到CSF中的gpi锚定蛋白明显减少，这支持了ALS患者GDE2活性受损。综上所述，本研究提供了GDE2分布和活性在ALS中被破坏的细胞和生化证据，支持了GDE2依赖性神经保护通路的失败导致疾病中神经退行性变和运动神经元丢失的观点。这些观察结果强调了gpi锚定蛋白通路的失调作为疾病发生和进展的候选介质，因此为ALS发病机制提供了新的见解。在线版本包含补充材料，可在10.1186/s40478-022-01376-x获得。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the viability of upper and lower motor neurons. Current options for treatment are limited, necessitating deeper understanding of the mechanisms underlying ALS pathogenesis. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane protein that acts on the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. GDE2 is required for the survival of spinal motor neurons but whether GDE2 neuroprotective activity is disrupted in ALS is not known. We utilized a combination of mouse models and patient post-mortem samples to evaluate GDE2 functionality in ALS. Haplogenetic reduction of GDE2 exacerbated motor neuron degeneration and loss in SOD1G93A mice but not in control SOD1WT transgenic animals, indicating that GDE2 neuroprotective function is diminished in the context of SOD1G93A. In tissue samples from patients with ALS, total levels of GDE2 protein were equivalent to healthy controls; however, membrane levels of GDE2 were substantially reduced. Indeed, GDE2 was found to aberrantly accumulate in intracellular compartments of ALS motor cortex, consistent with a disruption of GDE2 function at the cell surface. Supporting the impairment of GDE2 activity in ALS, tandem-mass-tag mass spectrometry revealed a pronounced reduction of GPI-anchored proteins released into the CSF of patients with ALS compared with control patients. Taken together, this study provides cellular and biochemical evidence that GDE2 distribution and activity is disrupted in ALS, supporting the notion that the failure of GDE2-dependent neuroprotective pathways contributes to neurodegeneration and motor neuron loss in disease. These observations highlight the dysregulation of GPI-anchored protein pathways as candidate mediators of disease onset and progression and accordingly, provide new insight into the mechanisms underlying ALS pathogenesis. The online version contains supplementary material available at 10.1186/s40478-022-01376-x.
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影响因子：
15.9
作者：
Kreutzberg, GW
通讯作者：
Kreutzberg, GW
影响因子：
4.8
作者：
Petrov D;Mansfield C;Moussy A;Hermine O
通讯作者：
Hermine O
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作者：
Da Cruz S;Cleveland DW
通讯作者：
Cleveland DW
影响因子：
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作者：
Matas-Rico, Elisa;van Veen, Michiel;Moolenaar, Wouter H.
通讯作者：
Moolenaar, Wouter H.
影响因子：
64.8
作者：
ROSEN, DR;SIDDIQUE, T;BROWN, RH
通讯作者：
BROWN, RH