Research press release


Nature Cell Biology

Defective synaptic contacts underlie neurodevelopmental disorders


ヒトでは、CDKL5をコードしている遺伝子の変異はすでに、レット症候群の中で神経発生異常や早発性てんかん、自閉症などの症状を示す特定の型と関連づけられていた。V Broccoliたちは、マウス脳ではCDKL5がシナプス結合領域に局在することを見いだした。さらに、ヒト細胞およびマウスモデルでCDKL5を大幅に減少させると、シナプス結合の正常な発生と神経細胞の正常な興奮性活動が阻害されることがわかった。また、マウスおよびヒトの細胞の両方で、CDKL5が細胞接着分子であるNGL-1のリン酸化による修飾に関わっていて(これによってNGL-1の結合活性が変更される)、シナプス結合の形成に不可欠なタンパク質との相互作用を助けていることも示された。


A way by which the protein kinase CDKL5 promotes dendritic spine growth and synaptic contacts during neuronal development is reported in a paper in Nature Cell Biology this week. The work outlines how depleted levels of this molecule disrupts neuronal activity and sheds light on how human mutations associated with neurodevelopmental disorders affect neuronal function.

In humans, mutations in the gene encoding CDKL5 were previously linked to a particular form of Rett syndrome that manifests itself through neurodevelopmental disorders, early-onset epilepsy and autism. Vania Broccoli and colleagues found that CDKL5 localizes to the zone of synaptic contacts in the mouse brain. They show that depleting CDKL5 in human cells and in a mouse model prevents the normal development of synaptic contacts and normal excitatory activity of neurons. They find, both in the mouse and human cells, that CDKL5 modifies the cell adhesion molecule NGL-1 by phosphorylation - which switches enzymes on and off, thereby altering their function and activity - in order to promote its interaction with proteins essential for the development of synaptic contacts.

The authors also note that pluripotent cells from people with CDKL5 mutations exhibit lower levels of NGL-1 phosphorylation and defects in synapse formation, similarly to mouse neurons in which CDKL5 was silenced.

doi: 10.1038/ncb2566


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