Details

Autor(en) / Beteiligte

• Yamakage, Yuko
• Kato, Michinao
• Hongo, Aya
• Ogino, Himari
• Ishii, Keisuke
• Ishizuka, Takumi
• Kamei, Takana
• Tsuiji, Hitomi
• Miyamoto, Tomomi
• Oishi, Hisashi
• Kohno, Takao
• Hattori, Mitsuharu

Titel

A disintegrin and metalloproteinase with thrombospondin motifs 2 cleaves and inactivates Reelin in the postnatal cerebral cortex and hippocampus, but not in the cerebellum

Ist Teil von

• Molecular and cellular neuroscience, 2019-10, Vol.100, p.103401-103401, Article 103401

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •ADAMTS-2, but not ADAMTS-14, cleaves Reelin as efficiently as ADAMTS-3.•ADAMTS-2 is expressed in the postnatal cerebrum and hippocampus.•The disintegrin domain is necessary for the Reelin-cleaving activity of ADAMTS-2 and -3.•Reelin function is augmented in the cerebrum and hippocampus of ADAMTS-2 KO mice.•Reelin metabolism in cerebellum is different from that in cerebrum and hippocampus.