Vanishing white matter: deregulated integrated stress response as therapy target
Vanishing white matter: deregulated integrated stress response as therapy target
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DOI：
10.1002/acn3.50826
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发表时间：
2019-07-18
影响因子：
5.3
通讯作者：
van der Knaap, Marjo S.
中科院分区：
文献类型：
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作者：
Abbink, Truus E. M.;Wisse, Lisanne E.;van der Knaap, Marjo S.
消失性白质（VWM）是一种致命的、压力敏感的脑白质营养不良，主要影响儿童，目前没有治疗方法。VWM是由真核起始因子2B （eIF2B）的隐性突变引起的，eIF2B在综合应激反应（ISR）过程中对mRNA翻译的起始和调控至关重要。突变降低了eIF2B的活性。VWM的病理机制尚不清楚。与eIF2B的管家功能相反，星形胶质细胞在VWM中受到选择性影响。研究目的之一是验证我们的假设，即大脑中特定mrna的翻译被eIF2B突变改变，主要影响星形胶质细胞。第二个目的是研究调节eIF2B活性是否可以改善这种改变的翻译并改善疾病。方法用eIF2B双等位错义突变重现人VWM的小鼠，用多染色体谱法筛选翻译改变的mrna。使用qPCR和免疫组织化学方法在VWM患者脑组织中验证了研究结果。给VWM小鼠注射复合ISRIB（“ISR抑制剂”）以增加eIF2B活性。评估其对翻译、神经病理学和临床症状的影响。结果与野生型小鼠相比，VWM小鼠大脑中ISR mrna的翻译变化最为显著；它们的表达水平与疾病严重程度相关。我们在VWM患者的大脑中证实了这些发现。ISRIB规范mRNA标记物的表达，改善脑白质病理，改善VWM小鼠的运动技能。目前的研究结果表明，ISR失调是VWM病理机制的核心，也是可行的治疗靶点。
Objective Vanishing white matter (VWM) is a fatal, stress-sensitive leukodystrophy that mainly affects children and is currently without treatment. VWM is caused by recessive mutations in eukaryotic initiation factor 2B (eIF2B) that is crucial for initiation of mRNA translation and its regulation during the integrated stress response (ISR). Mutations reduce eIF2B activity. VWM pathomechanisms remain unclear. In contrast with the housekeeping function of eIF2B, astrocytes are selectively affected in VWM. One study objective was to test our hypothesis that in the brain translation of specific mRNAs is altered by eIF2B mutations, impacting primarily astrocytes. The second objective was to investigate whether modulation of eIF2B activity could ameliorate this altered translation and improve the disease. Methods Mice with biallelic missense mutations in eIF2B that recapitulate human VWM were used to screen for mRNAs with altered translation in brain using polysomal profiling. Findings were verified in brain tissue from VWM patients using qPCR and immunohistochemistry. The compound ISRIB (for "ISR inhibitor") was administered to VWM mice to increase eIF2B activity. Its effect on translation, neuropathology, and clinical signs was assessed. Results In brains of VWM compared to wild-type mice we observed the most prominent changes in translation concerning ISR mRNAs; their expression levels correlated with disease severity. We substantiated these findings in VWM patients' brains. ISRIB normalized expression of mRNA markers, ameliorated brain white matter pathology and improved motor skills in VWM mice. Interpretation The present findings show that ISR deregulation is central in VWM pathomechanisms and a viable target for therapy.