Glial Metabolic Rewiring Promotes Axon Regeneration and Functional Recovery in the Central Nervous System.
Glial Metabolic Rewiring Promotes Axon Regeneration and Functional Recovery in the Central Nervous System.
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DOI：
10.1016/j.cmet.2020.08.015
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发表时间：
2020-11-03
期刊：
影响因子：
29
通讯作者：
Song Y
中科院分区：
文献类型：
--
作者：
Li F;Sami A;Noristani HN;Slattery K;Qiu J;Groves T;Wang S;Veerasammy K;Chen YX;Morales J;Haynes P;Sehgal A;He Y;Li S;Song Y
在成熟的中枢神经系统（CNS）的轴突不能再生轴突切断后，部分原因是由于抑制性的环境所构成的反应性胶质细胞产生星形胶质细胞瘢痕，硫酸软骨素蛋白多糖和髓鞘碎片。我们研究了这种抑制环境，表明它是可逆的，并取决于神经胶质细胞的代谢状态。我们发现，神经胶质细胞可以重新编程，以促进形态和功能再生后，中枢神经系统损伤的果蝇通过增加糖酵解。这种增强是由神经胶质衍生的代谢产物：L-乳酸和L-2-羟基戊二酸（L-2 HG）介导的。遗传/非遗传性增加或减少其生物活性促进或阻碍CNS轴突再生。L-乳酸和L-2 HG作用于神经元代谢型GABAB受体，促进cAMP信号传导。局部应用L-乳酸促进损伤脊髓皮质脊髓束轴突再生，导致成年小鼠行为恢复。我们的研究结果揭示了一种代谢开关，以规避神经胶质细胞的抑制，同时放大其治疗CNS损伤的有益作用。Li等揭示了神经胶质细胞的代谢状态与中枢神经系统轴突再生的失败有关。他们表明，抑制环境可以通过神经胶质细胞中有氧糖酵解的升高而基本上逆转，从而导致CNS中的轴突再生，这可能是进化上保守的。
Axons in the mature central nervous system (CNS) fail to regenerate after axotomy, partly due to the inhibitory environment constituted by reactive glial cells producing astrocytic scars, chondroitin sulfate proteoglycans and myelin debris. We investigated this inhibitory milieu, showing it is reversible and depends on glial metabolic status. We show that glia can be reprogrammed to promote morphological and functional regeneration after CNS injury in Drosophila via increased glycolysis. This enhancement is mediated by the glia derived metabolites: L-lactate and L-2-hydroxyglutarate (L-2HG). Genetically/pharmacologically increasing or reducing their bioactivity promoted or impeded CNS axon regeneration. L-lactate and L-2HG from glia acted on neuronal metabotropic GABAB receptors to boost cAMP signaling. Local application of L-lactate to injured spinal cord promoted corticospinal tract axon regeneration, leading to behavioral recovery in adult mice. Our findings revealed a metabolic switch to circumvent the inhibition of glia while amplifying their beneficial effects for treating CNS injuries. Li et al. reveal that the glial metabolic status is related to the failure of axon regeneration in the CNS. They show that the inhibitory environment can be essentially reversed by elevated aerobic glycolysis in glia, leading to axon regeneration in the CNS, which may be evolutionarily conserved.
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影响因子：
14.9
作者：
Babicki S;Arndt D;Marcu A;Liang Y;Grant JR;Maciejewski A;Wishart DS
通讯作者：
Wishart DS
影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
影响因子：
7.3
作者：
Hackley CR;Mazzoni EO;Blau J
通讯作者：
Blau J
DOI：
10.1073/pnas.1812941116
发表时间：
2019-02-26
影响因子：
11.1
作者：
Grenell, Allison;Wang, Yekai;Du, Jianhai
通讯作者：
Du, Jianhai
星形胶质细胞疤痕形成有助于中枢神经系统轴突再生。
影响因子：
64.8
作者：
Anderson MA;Burda JE;Ren Y;Ao Y;O'Shea TM;Kawaguchi R;Coppola G;Khakh BS;Deming TJ;Sofroniew MV
通讯作者：
Sofroniew MV