Riedel C J, Muraszko K M, Youle R J
Biochemistry Section, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, MD 20896.
Proc Natl Acad Sci U S A. 1990 Jul;87(13):5051-5. doi: 10.1073/pnas.87.13.5051.
CRM107 (crossreacting material 107), a double point mutant of diphtheria toxin that lacks receptor-binding activity, specifically kills cerebellar Purkinje cells in vivo. After injection into guinea pig cerebrospinal fluid, CRM107 (0.9 micrograms) and CRM107-monoclonal antibody conjugates (10 micrograms) kill up to 90% of the total Purkinje cell population with no detectable toxicity to other neurons. Animals exhibit ataxia, tremor, and abnormalities of posture and tone. Native diphtheria toxin, ricin, and ricin A chain do not cause ataxia and do not reduce the Purkinje cell population after intrathecal injection into guinea pigs at toxic or maximally tolerated doses. However, in rats, which will tolerate higher doses of diphtheria toxin than guinea pigs, Purkinje cells can be killed by both CRM107 and diphtheria toxin. A truncated mutant of diphtheria toxin, called CRM45, can also cause Purkinje cell killing but has additional toxicity not seen with CRM107. Animals treated with intrathecal CRM107 or CRM107 linked to antibodies may serve as models for Purkinje cell loss in a broad spectrum of human diseases and may be used to further study cerebellar physiology. Understanding the basis for the Purkinje cell sensitivity to CRM107 may illuminate other causes of Purkinje cell loss.
CRM107（交叉反应物质107）是一种缺乏受体结合活性的白喉毒素双点突变体，在体内能特异性地杀死小脑浦肯野细胞。将其注入豚鼠脑脊液后，CRM107（0.9微克）和CRM107 - 单克隆抗体偶联物（10微克）可杀死高达90%的浦肯野细胞总数，而对其他神经元无明显毒性。动物会出现共济失调、震颤以及姿势和肌张力异常。天然白喉毒素、蓖麻毒素和蓖麻毒素A链在以毒性或最大耐受剂量鞘内注射到豚鼠体内后，不会引起共济失调，也不会减少浦肯野细胞数量。然而，大鼠比豚鼠能耐受更高剂量的白喉毒素，在大鼠中，CRM107和白喉毒素均可杀死浦肯野细胞。一种名为CRM45的白喉毒素截短突变体也可导致浦肯野细胞死亡，但具有CRM107未表现出的额外毒性。经鞘内注射CRM107或与抗体相连的CRM107处理的动物，可作为多种人类疾病中浦肯野细胞丢失的模型，并可用于进一步研究小脑生理学。了解浦肯野细胞对CRM107敏感的基础，可能会揭示浦肯野细胞丢失的其他原因。
