MCT1 Deletion in Oligodendrocyte Lineage Cells Causes Late-Onset Hypomyelination and Axonal Degeneration.
MCT1 Deletion in Oligodendrocyte Lineage Cells Causes Late-Onset Hypomyelination and Axonal Degeneration.
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DOI：
10.1016/j.celrep.2020.108610
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发表时间：
2021-01-12
期刊：
影响因子：
8.8
通讯作者：
Rothstein JD
中科院分区：
文献类型：
--
作者：
Philips T;Mironova YA;Jouroukhin Y;Chew J;Vidensky S;Farah MH;Pletnikov MV;Bergles DE;Morrison BM;Rothstein JD
少突胶质细胞（OLs）通过表达单羧酸转运蛋白1 (MCT1)，在髓鞘形成和将能量代谢物乳酸和丙酮酸运送到轴突中发挥重要作用。最近的研究表明，OL MCT1的缺失导致轴突变性。然而，随着年龄的增长，MCT1在OLs中的广泛和慢性损失如何特异性地影响神经元能量稳态尚不清楚。为了回答这个问题，产生了MCT1条件无效小鼠，允许ol特异性MCT1消融。我们观察到MCT1的丢失对于生命早期正常的髓鞘形成和轴突能量稳态是必不可少的。相比之下，随着年龄的增长，OL谱系MCT1表达的丧失会导致显著的轴突变性，并伴有髓鞘退化。这些数据支持了MCT1在老化的中枢神经系统（CNS）中对神经元能量稳态很重要的假设。随着年龄的增长，OL MCT1的减少可能会增加神经退行性疾病中轴突变性和萎缩的风险。Philips等人利用MCT1的条件细胞特异性缺失研究发现，少突胶质细胞系细胞实际上对于早期正常的髓鞘形成和轴突能量稳态是必不可少的，但基于少突胶质乳酸/MCT1的支持对神经系统的衰老至关重要。
Oligodendrocytes (OLs) are important for myelination and shuttling energy metabolites lactate and pyruvate toward axons through their expression of monocarboxylate transporter 1 (MCT1). Recent studies suggest that loss of OL MCT1 causes axonal degeneration. However, it is unknown how widespread and chronic loss of MCT1 in OLs specifically affects neuronal energy homeostasis with aging. To answer this, MCT1 conditional null mice were generated that allow for OL-specific MCT1 ablation. We observe that MCT1 loss from OL lineage cells is dispensable for normal myelination and axonal energy homeostasis early in life. By contrast, loss of OL lineage MCT1 expression with aging leads to significant axonal degeneration with concomitant hypomyelination. These data support the hypothesis that MCT1 is important for neuronal energy homeostasis in the aging central nervous system (CNS). The reduction in OL MCT1 that occurs with aging may enhance the risk for axonal degeneration and atrophy in neurodegenerative diseases. Using conditional cell-specific deletion of MCT1, Philips et al. learn that oligodendrocyte lineage cells are actually dispensable for normal myelination and axonal energy homeostasis during early life but that the oligodendroglial lactate/MCT1-based support is critical for the aging of the nervous system.
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