Hevin–calcyon interaction promotes synaptic reorganization after brain injury

Jong Heon Kim, Hyun Gug Jung, Ajung Kim, Hyun Soo Shim, Seung Jae Hyeon, Young Sun Lee, Jin Han, Jong Hoon Jung, Jaekwang Lee, Hoon Ryu, Jae Yong Park, Eun Mi Hwang, Kyoungho Suk

Research output: Contribution to journalArticlepeer-review

Abstract

Hevin, also known as SPARC-like protein 1 (SPARCL1 or SC1), is a synaptogenic protein secreted by astrocytes and modulates the formation of glutamatergic synapses in the developing brain by interacting with synaptic adhesion proteins, such as neurexin and neuroligin. Here, we identified the neuron-specific vesicular protein calcyon as a novel interaction partner of hevin and demonstrated that this interaction played a pivotal role in synaptic reorganization after an injury in the mature brain. Astrocytic hevin was upregulated post-injury in a photothrombotic stroke model. Hevin was fragmented by MMP3 induced during the acute stage of brain injury, and this process was associated with severe gliosis. At the late stage, the functional hevin level was restored as MMP3 expression decreased. The C-terminus of hevin interacted with the N-terminus of calcyon. By using RNAi and binding competitor peptides in an ischemic brain injury model, we showed that this interaction was crucial in synaptic and functional recoveries in the sensory-motor cortex, based on histological and electrophysiological analyses. Regulated expression of hevin and calcyon and interaction between them were confirmed in a mouse model of traumatic brain injury and patients with chronic traumatic encephalopathy. Our study provides direct evidence for the causal relationship between the hevin–calcyon interaction and synaptic reorganization after brain injury. This neuron-glia interaction can be exploited to modulate synaptic reorganization under various neurological conditions.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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