Currently, there are no official treatments for reversing spinal cord damage . There is no cure for the more than 5 million senior citizens who have Alzheimer’s disease . In fact, one of medicine’s greatest adversities is the restoration of function after nerve injury or degeneration . Nevertheless, research is still being conducted and a lead has been found regarding possible treatments for neurological injuries, diseases, and other conditions: fusogens. Fusogens are glycoproteins which station themselves inside or on cell membranes and interact with other cell membranes to overcome, control, and regulate the forces that inhibit spontaneous membrane fusion. Besides neurological applications, fusogens have also been found in promoting muscle cell fusion, sperm-egg fusion, macrophage fusion, cancer metastasis, epithelial cell fusion for eye lens formation, and other implementations . However, focusing on the neurological aspect, a wide variety of fusogen classes allow for multiple medical issues to be mitigated. With further experimentation, the modern healthcare field may experience a variety of new treatments for “impossible” situations thanks to fusogens.
Epithelial Fusion Failure-1 and Anchor Cell Fusion Failure-1 for Axonal Fusion
Axonal fusion mechanisms are crucial to any regenerative goal in the body; they represent means of functional restoration after neuronal injury. Two studies performed in 2017 by Basu et al. and Abay et al. indicate that axonal fusion in Caenorhabditis elegans, a species of roundworm, repaired severed mechanosensory neurons, restoring full function. Axonal fusion requires the damaged axon to undergo regrowth, reconnection, and fusion processes. To regrow, the proximal axon must make its way towards the distal fragment and then make contact to initiate reconnection. This occurs when phosphatidylserine (PS) attaches itself to the exterior membrane of the severed axonal segments to function as a rescue signal after neuronal injury. Lipid binding proteins TTR-52 and NRF-5 bind with the exposed PS. The two parts of the axon must merge to create a continuous axonal membrane in order to fuse. CED-6 and PSR-1 molecules are involved with reconnection, but fusogens Epithelial Fusion Failure-1 (EFF-1) and Anchor Cell Fusion Failure-1 (AFF-1) regulate the majority of axonal fusion in C. elegans. EFF-1 proteins are inserted into both ends of the severed axon, so that the fusogen can form bonds across the gap. The proteins then rapidly shift into location and accumulate at the tips of the severed axon, mediating fusion for segment reconnection. The combined effects of EFF-1 and AFF-1 promote dendritic repair due to the disrupted connection from the severed axon afterward. With more research, Wallerian degeneration, the active degeneration of the neuron distal from the injury site caused by damage to nerve fibers, can be more easily prevented . The graphic below further explains how the mentioned glycoproteins facilitate axonal fusion after transection.
Polyethylene Glycol for Spinal Cord Injuries
Moving from minor neuronal injuries, spinal cord injuries (SCI) on the other hand disrupt motor, sensory, and autonomic functions within the body. There are no clinical treatments successful at repairing the damage to restore motor function. However, a relatively inexpensive and water-soluble polymer has been researched for its potential benefits in medicine. Polyethylene glycol (PEG), a fusogenic chemical, has been noted for immediately repairing physical damage, promoting axonal regeneration, restoring synaptic connections with target tissues, and overall, stimulating injury repair. It can repair compromised neuronal membranes by fusing the cell membranes together. Although this fusion process is unclear, there are two hypotheses as to how it occurs: PEG dehydrates the involved cell membranes which allow lipid elements to cross over into each other, or PEG reduces the surface tensions and improves both membranes’ fluidity so they seal to each other . Either hypothesis requires the general prerequisite that the two involved membranes are in close proximity . This allows for their phospholipid membranes to rearrange together by cell-aggregating agents or to diminish repellent charges between the two membranes by using membrane-modifying agents which change the individual surface charges .
After SCI or any damage to the central nervous system, a glial scar forms around the injured area in order to protect it, inhibiting the growth of new axons and synapses. Certain biomaterials have been able to fill these lesions, delivering new cells to replace the dead ones, or to release drugs which improved damage from inflammation and increased cell invasion . Current techniques of nerve injury repair do not address the physical disruption in the axonal membrane . However, PEG was discovered to immediately repair physical damage in the spinal cord, reducing local glial scar formation in a five-step process: trimming of severed ends, prevention of plasmalemma sealing, rejoining the segments with microstructures. This results in the inducement of membrane fusion between segments with PEG, repairing residual membrane disruptions mediated by vesicles .
Although the use of polyethylene glycol in medical settings is premature, multiple laboratory and clinical trials have proven successful. Ren et al. performed laminectomies at the T-10 vertebra in rats. Immediately, PEG was directly applied to the transection point while the control group received saline applications. The goal was to refuse the thoracic spinal cord. Over a period of 28 days, the PEG-treated group showed better blood-brain barrier scores than the control group. The PEG-treated group showed signs of recovery in increased somatosensory evoked potential (SSEP) waveforms while the saline-treated group showed no improvement. Direct tensor imagery showed that the significance in differences of recovery between the PEG and saline-treated groups were possibly affected by the tissue continuity that the PEG was able to achieve in refusing the spinal cord. Ren et al. noted that PEG did not actually prevent the formation of the glial scar, but by promoting axonal regeneration, the severed spinal cord ends were able to bridge together, improving function restoration. Liu et al. applied PEG at the transection site of the spinal cord of a dog at T-10. On a scale of 0-15, 0 being no hindlimb movement, the PEG-treated group had a median blood-brain barrier score of 8, whilst the control group had a median score of 3. Tensor imaging showed fiber reconstitution of the spinal cord and increased SSEP waveforms in the PEG-treated group. Kim et al. conducted cervical laminectomies at C5 in rats to model SCIs and then applied PEG or saline. Motor-evoked potential (MEP) measurements showed increased amplitudes at only 1 hour after the injury. The results for the PEG trials for SCIs in animals suggested additional benefits of early and direct application of PEG to the transection in the spinal cord which would lessen neural damage and further the regenerative process .
In 2016, Bamba et al. were the first to clinically-use PEG-fusion in humans. They were able to repair four fingers of two teenagers after complete nerve transection injuries, and within twelve hours, the nerves were fused with the five-step process. The success of the PEG-treatment sparked discussion over its potential usefulness for all human nerve injuries. Not only could it be applied to the spinal cord, but its different applications could expand into the peripheral nervous system to aid in functional recovery for all nerves .
Amyloid-β Cells for Alzheimer’s Disease
In other cases, fusogens have been determined to actually be more harmful to our nervous system. Alzheimer’s is a neurodegenerative disease leading to progressive loss of memory and overall cognitive decline, resulting in death. Even though it is one of the most studied pathologies, it is not fully understood on a molecular level and there is no available cure. However, it has been discovered that patients with Alzheimer’s have extracellular deposits of amyloid β-peptide (Aβ) within the brain that are generated from the proteolytic cleavage of the glycoprotein, β-amyloid precursor protein (APP) . These cells are neurotoxic and are thought to play a major role in neural cell death brought on by Alzheimer’s through the disruption of cellular activity; Aβ-peptides mediate membrane fusion and induce high membrane responses such as structural reorganization. They directly change the biophysical properties of cell membrane fluidity by modifying membrane fluctuation, fusion, and transformation and disrupting vital organelle activities, like mitochondrial fission and fusion . Overall, virtually all pathobiology researchers for Alzheimer’s disease, over the last 15 years, support the hypothesis that almost all forms of Alzheimer’s disease are initiated by the progressive cerebral accumulation of Aβ-protein which sets-off a multicellular cascade that results in microgliosis, astrocytosis, neuritic dystrophy, neuronal dysfunction, neuronal death, and synaptic alterations that lead to impaired neurotransmitter activity and cognitive function. One benefit of this hypothesis is that it lays out specific molecular targets that can be screened against to develop treatments to prevent Alzheimer’s disease by preventing cerebral β-amyloidosis .
The clinical use of fusogens for medical treatment is still in its beginning and experimental stages. However, in-depth research has proven that these membrane-fusion inducing glycoproteins have the capacity to make axonal fusion more efficient and to reverse spinal cord injuries, as well as to better treat Alzheimer’s disease. With more experimentation, fusogens may well become standard and successful treatment options for these fatal diseases. This article only analyzed the treatment potentials of four fusogens: Epithelial Fusion Failure-1 and Anchor cell Fusion Failure-1 for axonal fusion, polyethylene glycol for spinal cord injuries, and amyloid-β for Alzheimer’s disease. More research and study expansion into the effects of other glycoproteins has the potential to reveal even more potential benefits of fusogens and possibly bring about groundbreaking treatments for widespread disorders.
Hi there! My name is Charlene Cai and I'm apart of the Class of 2022 at the Academy for Health and Medical Sciences in New Jersey! Besides reading up on the latest medical breakthroughs, you can find me volunteering at my local hospital, virtually tutoring kids, playing volleyball with my teammates, speaking at a Forensics Speech Tournament, or just watching Netflix.