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Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice.
Acta Neuropathologica Communications ( IF 7.1 ) Pub Date : 2020-09-14 , DOI: 10.1186/s40478-020-01032-2
Manuela Lehmann 1 , Matthew Marklund 2 , Anna-Lena Bolender 1 , Elaheh E Bidhendi 1 , Per Zetterström 3 , Peter M Andersen 1 , Thomas Brännström 2 , Stefan L Marklund 3 , Jonathan D Gilthorpe 4 , Ulrika Nordström 1
Affiliation  

Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.

中文翻译:

聚集体选择性抗体可减轻种子聚集,但不会自发演变为SOD1 ALS模型小鼠的疾病。

越来越多的证据表明,运动神经元疾病肌萎缩性侧索硬化症(ALS)的传播涉及疾病相关蛋白的致病性聚集,这些蛋白以a病毒样方式传播。我们已经确定了人类超氧化物歧化酶1(hSOD1)的两个聚合株,它们出现在SOD1介导的ALS转基因小鼠模型的CNS中。当接种到成年hSOD1转基因小鼠的脊髓中时,这两种菌株都传播模板定向的聚集和过早的致命性麻痹。病原体聚集的这种传播可能是免疫治疗干预的潜在目标。在这里,我们生成了针对hSOD1聚合菌株中暴露的表位的小鼠单克隆抗体(mAb),并鉴定了针对hSOD1(αSOD1143–153)氨基酸143–153 C末端的聚合选择性单克隆抗体。接种前用αSOD1143-153对种子进行预温育,以及每周腹膜内(ip)给药均可减弱病原体聚集的传播,并延长接种了种子的hSOD1G85R Tg小鼠的存活期。相比之下,施用针对aa 65-72的mAb(αSOD165-72)表现出对单体无序hSOD1的高亲和力,则产生不利影响,并加剧了种子诱发的过早ALS样疾病。尽管单克隆抗体在脑脊液中的浓度相似,但在脊髓匀浆中仅发现αSOD1143–153与聚集的hSOD1相关。我们的结果表明,聚集体选择性免疫治疗方法可以抑制ALS中病原性聚集的种子传播。但是,长期服用αSOD1143-153不能延长未接种hSOD1G85R Tg小鼠的寿命。
更新日期:2020-09-14
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