Endothelial miR-15a/16-1 Regulation of SYNE1 Mediates Structural and Functional Recovery after Traumatic Brain Injury

Area of Science:

• Neuroscience
• Molecular Biology
• Vascular Biology

Background:

• Traumatic brain injury (TBI) impairs blood-brain barrier (BBB) function and endothelial cells, causing lasting neurological deficits.
• The role of microRNAs (miRNAs) in TBI-induced endothelial dysfunction and long-term recovery is not fully understood.
• Previous studies suggest miR-15a/16-1 deletion offers neuroprotection in brain injury models.

Purpose of the Study:

• To investigate the role of endothelial miR-15a/16-1 in mediating structural and functional recovery after TBI.
• To identify downstream molecular targets of miR-15a/16-1 in brain endothelial cells following TBI.
• To explore the translational potential of targeting the miR-15a/16-1 pathway for TBI treatment.

Main Methods:

• Endothelial cell-specific deletion of miR-15a/16-1 in a mouse TBI model.
• Assessment of BBB leakage, white and gray matter integrity, and sensorimotor/cognitive function.
• Transcriptomic profiling, in-silico analysis, 3'-UTR luciferase assays to identify and validate miR-15a/16-1 targets.
• AAV-mediated knockdown of identified targets in endothelial cells.
• Single-cell RNA-sequencing analysis of human TBI tissue.

Main Results:

• Endothelial-specific deletion of miR-15a/16-1 reduced acute BBB leakage and preserved brain matter integrity post-TBI.
• This deletion accelerated sensorimotor and cognitive recovery in TBI models.
• SYNE1 was identified as a direct downstream target of miR-15a/16-1 in endothelial cells.
• Knockdown of SYNE1 in endothelial cells abolished the neurorestorative effects of miR-15a/16-1 deletion.
• Human TBI tissues showed reduced SYNE1 expression in endothelial cells within the contusion core.

Conclusions:

• A novel miR-15a/16-1-SYNE1 axis in brain endothelial cells is critical for neurorestoration after TBI.
• Targeting this axis promotes BBB repair and neurological recovery, offering therapeutic potential for TBI.
• Endothelial SYNE1 downregulation is implicated in TBI pathophysiology.