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Abstract
The brain of mammals lacks a significant ability to regenerate neurons and is thus particularly vulnerable. To protect the brain from injury and disease, damage control by astrocytes through astrogliosis and scar formation is vital. Here, we show that brain injury in mice triggers an immediate upregulation of the actin-binding protein Drebrin (DBN) in astrocytes, which is essential for scar formation and maintenance of astrocyte reactivity. In turn, DBN loss leads to defective astrocyte scar formation and excessive neurodegeneration following brain injuries. At the cellular level, we show that DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds, facilitating the formation of RAB8-positive membrane tubules. This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesion mediators, such as β1-integrin. Our work shows that DBN-mediated membrane trafficking in astrocytes is an important neuroprotective mechanism following traumatic brain injury in mice.
Highlights
The brain of mammals lacks a significant ability to regenerate neurons and is vulnerable
We did not detect any DBN signals in astrocytes, high DBN levels were found in dendritic spines of neighboring neurons (Fig. 1A)
We show that (1) under physiological conditions, DBN protein is not expressed in astrocytes; its injury-induced upregulation in reactive astrocytes is required for the coordinated formation and maintenance of astrocyte scars, demonstrating its essential role in effective tissue protection in the brain
Summary
The brain of mammals lacks a significant ability to regenerate neurons and is vulnerable. We show that DBN switches actin homeostasis from ARP2/3-dependent arrays to microtubule-compatible scaffolds, facilitating the formation of RAB8-positive membrane tubules This injury-specific RAB8 membrane compartment serves as hub for the trafficking of surface proteins involved in astrogliosis and adhesion mediators, such as β1-integrin. DBN provides a key switch to alter actin network homeostasis, which prepares the foundation for tubular endosomes, enabling polarized membrane trafficking of crucial surface receptors. In this role, DBN controls reactive astrogliosis required to form astrocyte scars and to protect the susceptible CNS from traumatic brain injury
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