Reelin plays important roles in regulating neuronal development, modulating synaptic function, and counteracting amyloid β toxicity. A specific proteolytic cleavage (N-t cleavage) of Reelin abolishes its biological activity. We recently identified ADAMTS-3 (a disintegrin and metalloproteinase with thrombospondin motifs 3) as the major N-t cleavage enzyme in the embryonic and early postnatal brain. The contribution of other proteases, particularly in the postnatal brain, has not been demonstrated in vivo. ADAMTS-2, -3 and -14 share similar domain structures and substrate specificity, raising the possibility that ADAMTS-2 and -14 may cleave Reelin. We found that recombinant ADAMTS-2 protein expressed in cultured cell lines cleaves Reelin at the N-t site as efficiently as ADAMTS-3 while recombinant ADAMTS-14 hardly cleaves Reelin. The disintegrin domain is necessary for the Reelin-cleaving activity of ADAMTS-2 and -3. ADAMTS-2 is expressed in the adult brain at approximately the same level as ADAMTS-3. We generated ADAMTS-2 knockout (KO) mice and found that ADAMTS-2 significantly contributes to the N-t cleavage and inactivation of Reelin in the postnatal cerebral cortex and hippocampus, but much less in the cerebellum. Therefore, it was suggested that ADAMTS-2 can be a therapeutic target for adult brain disorders such as schizophrenia and Alzheimer's disease.

中文翻译：

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带有血小板反应蛋白基序的整合素和金属蛋白酶2在产后大脑皮层和海马体中切开并使Reelin失活，但在小脑中则没有。

Reelin在调节神经元发育，调节突触功能和抵抗淀粉样β毒性中起重要作用。Reelin的特定蛋白水解裂解（Nt裂解）消除了其生物学活性。我们最近确定ADAMTS-3（一种具有血小板反应蛋白基序3的整合素和金属蛋白酶）是胚胎和出生后早期脑中的主要Nt裂解酶。尚未在体内证明其他蛋白酶的作用，特别是在产后大脑中。ADAMTS-2，-3和-14共享相似的域结构和底物特异性，从而提高了ADAMTS-2和-14切割Reelin的可能性。我们发现，在培养的细胞系中表达的重组ADAMTS-2蛋白在Nt位点裂解Reelin的效率与ADAMTS-3相同，而重组ADAMTS-14几乎不裂解Reelin。Disintegrin域对于ADAMTS-2和-3的Reelin切割活性是必需的。ADAMTS-2在成人大脑中的表达水平与ADAMTS-3大致相同。我们生成了ADAMTS-2基因敲除（KO）小鼠，发现ADAMTS-2在产后大脑皮层和海马中显着促进Nt裂解和Reelin失活，而在小脑中则少得多。因此，建议ADAMTS-2可以作为成人脑疾病如精神分裂症和阿尔茨海默氏病的治疗靶标。我们生成了ADAMTS-2基因敲除（KO）小鼠，发现ADAMTS-2在产后大脑皮层和海马中显着促进Nt裂解和Reelin失活，而在小脑中则少得多。因此，建议ADAMTS-2可以作为成人脑疾病如精神分裂症和阿尔茨海默氏病的治疗靶标。我们生成了ADAMTS-2基因敲除（KO）小鼠，发现ADAMTS-2在产后大脑皮层和海马中显着促进Nt裂解和Reelin失活，而在小脑中则少得多。因此，建议ADAMTS-2可以作为成人脑疾病如精神分裂症和阿尔茨海默氏病的治疗靶标。