Summary: Scientists have identified two proteins that limit microglial reactivity, prevent scar formation after brain injury, and enable regeneration of neural tissue in a zebrafish model.
Source: LMU
LMU researchers show in a zebrafish model that two proteins suppress scar formation in the brain and thereby enhance the tissue’s ability to regenerate.
Most tissues in the body renew their cells continuously, but the number of neurons in the adult human brain and spinal cord remains largely constant. Although new neurons can be produced in adult mammals, previous work by LMU scientist Professor Magdalena Götz and others has shown that newly formed neurons usually fail to integrate into existing brain circuits and survive after injury, except in two specialized brain niches.
A key reason for this limited regenerative capacity is the response of glial cells, the brain’s support cells. In particular, microglia—the brain’s immune cells—become highly reactive after injury, triggering inflammation and forming scar tissue that walls off the damaged area. While that scarring protects surrounding tissue in the short term, it also blocks the proper incorporation and survival of new neurons over time. Until now, the mechanisms that control this switch from a protective to a chronically reactive state were not well understood.
A team led by LMU cell biologist Professor Jovica Ninkovic reports in Nature Neuroscience that limiting microglial reactivity is essential to prevent chronic inflammation and scarring and is therefore a critical factor in enabling scarless regeneration.
How central nervous system injuries heal in zebrafish
Unlike mammals, zebrafish possess remarkable regenerative ability in the central nervous system (CNS). When the zebrafish brain is injured, neural stem cells produce long-lived neurons and other cell types that rebuild the damaged tissue. Importantly, glial reactivity in zebrafish is transient after injury, a feature that allows new neurons to integrate into the damaged region and restore function.
“We aimed to identify the key differences between zebrafish and mammals so we could discover which signaling pathways in the human brain block regeneration—and how those pathways might be modulated,” explains Ninkovic.
The researchers produced controlled CNS lesions in zebrafish to trigger a microglial response and then analyzed molecular changes in the injured tissue. They observed that activated microglia in lesions accumulated lipid droplets and condensates of the protein TDP-43, a protein previously linked mainly to neurodegenerative diseases.
The team also identified granulin, another protein, as a critical regulator in this process. Granulin promoted the clearance of both lipid droplets and TDP-43 condensates, enabling microglia to revert from their activated state back to a resting state. When this clearance happened, the zebrafish tissue regenerated without forming a lasting scar. By contrast, zebrafish engineered to lack granulin showed poor regenerative outcomes and persistent scarring, resembling the limited healing seen in mammals.
“These findings indicate that granulin plays a key role in allowing nerve tissue to regenerate in zebrafish by helping microglia resolve their activated state,” says Ninkovic.
Translating basic findings toward therapeutic ideas
To explore whether the mechanisms revealed in zebrafish are relevant to humans, the researchers examined postmortem cortical brain tissue from patients who had experienced traumatic brain injury. They found a similar correlation between microglial activation and the presence of lipid droplets and TDP-43 condensates in the lesions, suggesting that the same pathways operate in human tissue.
Based on these parallels, the LMU team sees potential for new therapeutic strategies that reduce harmful microglial reactivity and promote scarless repair. As a next step, Ninkovic plans to test whether known low-molecular-weight compounds can inhibit the signaling pathways that drive microglial activation and thus improve healing after neural injury. These candidate compounds will first be evaluated in zebrafish models during preclinical testing.
About this neuroscience research news
Author: Press Office
Source: LMU
Contact: Press Office – LMU
Image: The image is in the public domain
Original Research: Closed access.
Title: “TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury” by Alessandro Zambusi et al., published in Nature Neuroscience
Abstract
TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury
Reducing the activation of pathology-associated microglia is crucial for preventing chronic inflammation and tissue scarring after CNS injury.
Using a controlled stab-wound injury model in zebrafish, the study identifies an injury-induced microglial state marked by the buildup of lipid droplets and TAR DNA-binding protein 43 (TDP-43)+ condensates.
Clearance of both lipid droplets and TDP-43+ condensates mediated by granulin was necessary and sufficient to restore microglia to their basal, nonactivated state and to achieve scarless regeneration.
Furthermore, analysis of postmortem cortical tissue from patients with traumatic brain injury revealed that higher degrees of microglial activation were associated with accumulation of lipid droplets and TDP-43+ condensates, mirroring the zebrafish findings.
Together, the results reveal a conserved mechanism for returning microglia to a nonreactive state after injury, offering a promising avenue for therapeutic development aimed at enhancing repair and preventing chronic scarring in the injured human brain.