Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare, slowly progressive white matter disease caused by mutations in the mitochondrial aspartyl-tRNA synthetase (mt-AspRS, or DARS2). While patients show characteristic MRI T2 signal abnormalities throughout the cerebral white matter, brainstem, and spinal cord, the phenotypic spectrum is broad and a multitude of gene variants have been associated with the disease. Here, Dars2 disruption in CamKIIα-expressing cortical and hippocampal neurons results in slowly progressive increases in behavioral activity at five months, and culminating by nine months as severe brain atrophy, behavioral dysfunction, reduced corpus callosum thickness, and microglial morphology indicative of neuroinflammation. Interestingly, RNAseq based gene expression studies performed prior to the presentation of this severe phenotype reveal the upregulation of several pathways involved in immune activation, cytokine production and signaling, and defense response regulation. RNA transcript analysis demonstrates that activation of immune and cell stress pathways are initiated in advance of a behavioral phenotype and cerebral deficits. An understanding of these pathways and their contribution to significant neuronal loss in CamKII-Dars2 deficient mice may aid in deciphering mechanisms of LBSL pathology.

中文翻译：

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小鼠体内 mt-AspRS 的神经元消融会在严重且进行性的皮质和行为破坏之前诱导免疫途径激活。


脑干和脊髓受累及乳酸升高的白质脑病 (LBSL) 是一种罕见的、缓慢进展的白质疾病，由线粒体天冬氨酰-tRNA 合成酶（mt-AspRS 或 DARS2）突变引起。虽然患者在整个大脑白质、脑干和脊髓中表现出特征性 MRI T2 信号异常，但表型谱很广泛，并且多种基因变异与该疾病相关。在这里，表达 CamKIIα 的皮质和海马神经元中的 Dars2 破坏导致五个月时行为活动缓慢进行性增加，并在九个月时达到顶峰，出现严重的脑萎缩、行为功能障碍、胼胝体厚度减少以及表明神经炎症的小胶质细胞形态。有趣的是，在出现这种严重表型之前进行的基于 RNAseq 的基因表达研究揭示了涉及免疫激活、细胞因子产生和信号传导以及防御反应调节的多种途径的上调。 RNA 转录物分析表明，免疫和细胞应激途径的激活是在行为表型和大脑缺陷之前启动的。了解这些途径及其对 CamKII-Dars2 缺陷小鼠中显着神经元损失的贡献可能有助于破译 LBSL 病理学机制。