Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2
Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2
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DOI：
10.1016/j.neuron.2020.03.028
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发表时间：
2020-07-08
期刊：
影响因子：
16.2
通讯作者：
Reversade, Bruno
中科院分区：
文献类型：
--
作者：
Escande-Beillard, Nathalie;Loh, Abigail;Reversade, Bruno
缺乏PYCR2(一种合成脯氨酸的线粒体酶)的患者，出生后表现为退行性小头畸形伴髓鞘减少。在这里，我们报道了PYCR2脱辅酶的晶体结构，并表明一个新的种系P.Gly249Val突变位于二聚体界面，降低了它的酶活性。我们发现，在小鼠中敲除PYCR2会复制人类的症状，并耗尽神经谱系中PYCR1的水平。对PYCR2突变小鼠和患者大脑中神经递质的原位定量显示，这是由过量的大脑甘氨酸引起的脑病的特征。从机制上讲，我们证明了PYCR2的缺失上调了负责甘氨酸合成的SHMT2。这种高血糖可以被SHMT2基因敲除部分逆转，SHMT2基因敲除可以挽救培养的Pycr2基因敲除神经元的轴突珠状和轴突长度。我们的发现确定甘氨酸代谢途径可能是缓解PYCR2突变患者神经症状的一个可能的干预点。
Patients lacking PYCR2, a mitochondrial enzyme that synthesizes proline, display postnatal degenerative microcephaly with hypomyelination. Here we report the crystal structure of the PYCR2 apo-enzyme and show that a novel germline p.Gly249Val mutation lies at the dimer interface and lowers its enzymatic activity. We find that knocking out Pycr2 in mice phenocopies the human disorder and depletes PYCR1 levels in neural lineages. In situ quantification of neurotransmitters in the brains of PYCR2 mutant mice and patients revealed a signature of encephalopathy driven by excessive cerebral glycine. Mechanistically, we demonstrate that loss of PYCR2 upregulates SHMT2, which is responsible for glycine synthesis. This hyperglycemia could be partially reversed by SHMT2 knockdown, which rescued the axonal beading and neurite lengths of cultured Pycr2 knockout neurons. Our findings identify the glycine metabolic pathway as a possible intervention point to alleviate the neurological symptoms of PYCR2-mutant patients.