Novel Molecular Pathway Offers Potential Breakthrough in Stroke Treatment
BOSTON, MA – A newly discovered interaction between two proteins, mitofusin 2 (MFN2) and BAG6, demonstrates a synergistic protective effect against brain damage following stroke, offering a promising new avenue for therapeutic intervention. Research published today details how bolstering this molecular partnership significantly reduces damaging reactive oxygen species (ROS) and restores critical cellular processes in models of ischemic stroke.
Stroke remains a leading cause of long-term disability and death worldwide, affecting millions annually. Current treatments are limited, often focusing on rapid restoration of blood flow, but offering little to mitigate the cellular damage that occurs during and after the initial event.This study, conducted using both mouse models and human cell lines, identifies a previously unknown mechanism by which MFN2, a protein vital for mitochondrial health, exerts its neuroprotective effects – specifically, through its interaction with BAG6. the findings suggest that targeting this MFN2-BAG6 pathway could dramatically improve stroke outcomes by minimizing cellular stress and promoting recovery.
researchers found that reducing MFN2 levels worsened brain injury in mice subjected to middle cerebral artery occlusion, a common model of stroke, while increasing MFN2 levels provided protection. Crucially, this protective effect was significantly amplified when BAG6 was also overexpressed. Experiments revealed that MFN2 and BAG6 directly interact, and that BAG6 mimics the beneficial effects of MFN2, decreasing ROS levels and stabilizing mitochondrial function.
the study employed a range of techniques, including conditional knockout mice, siRNA-mediated knockdown, adeno-associated viral vectors, plasmid vectors, 2,3,5-triphenyltetrazolium chloride staining, RealTime Apoptosis and Necrosis assays, and Western blot analysis to rigorously assess the impact of MFN2 and BAG6 manipulation.Neurological deficits were evaluated using a 48-point score and rotarod tests.
Further investigation showed that MFN2 deficiency led to increased ROS and impaired autophagy – a cellular “self-cleaning” process crucial for removing damaged components. Conversely, MFN2 overexpression reduced ROS and restored autophagic flux. The combined overexpression of MFN2 and BAG6 resulted in a synergistic reduction of ROS, improved mitochondrial function, and modulated autophagy, leading to a ample decrease in brain injury.
These findings position the MFN2-BAG6 axis as a compelling target for the advancement of novel stroke therapies. future research will focus on translating these pre-clinical results into effective treatments for human stroke patients.
Keywords: autophagy; glucose; infarction, middle cerebral artery; ischemic stroke; triphenyltetrazolium.
