A research project about an extremely complex process of interrupting nerve cell suicide generated some nice press in the past couple of days. This coverage, which offers a sort of high-altitude view of the work, was generated by a well-rendered media release from the Salk Institute: “Salk Scientist Discovers Novel Mechanism in Spinal Cord Injury
.” You know your press release was a good one when news outlets reprint it verbatim, and that’s what I’ve seen in this case.
That’s beside the point but it is interesting to see which papers in the daily flow of biological arcanum get blessed with a headline and a chance for some media daylight. I am drawn to this one since it was partly funded by the Reeve Foundation and since one of the authors is Fred H. Gage, Ph.D., who sits on a science advisory panel for the Reeve International Research Consortium on Spinal Cord Injury and who, until last year, ran one of those Consortium labs.
This research focuses on a protein called p45 and a process called apoptosis. P45 is a sort of signaling messenger between cells. Apoptosis – from the Greek for “falling off,” as in leaves falling off a plant – is the term for programmed cell death. Cells can die by necrosis, that is, by the hand of outside forces, or they can die by their own hand, as in apoptosis. Don’t think this is a rare phenomenon. Apoptosis happens billions of time a day in our bodies as old cells are replaced. The issue in this case is that nerve trauma initiates a giant wave of suicidal nerve cells. The thinking is, if this cascade of death can be slowed down and those nerve cells can be preserved, the chances for recovery therefore increases.
The title of the new paper is “P45 Forms a Complex with FADD and Promotes Neuronal Cell Survival Following Spinal Cord Injury
.” The trail gets a little steep now. FADD stands for fas-associated death domain (DD) adaptor. Fas is a cell surface receptor; it hooks up with other protein signals called caspases and is mainly concerned with setting off the biochemical cascade leading to cell death. In spinal cord injury, Fas and FADD are up-regulated in the area around the injury site; both not only play a role in promoting cell death but actively prevent functional recovery. Says the paper, “We show that p45 forms a complex with FADD and diminishes Fas-FADD mediated death signaling.”
The group, led by scientists Kuo-Fen Lee and Tsung Chang Sung, used a mouse model that was genetically tricked to overexpress p45. The animals received stab wound spinal cord injuries. They ran the animals through some behavior tests and compared them to controls. I’m boiling this down to the bare essentials, but the process seems to have worked.
Said the paper: “These results support the finding that p45 over-expression reduces injury-induced cell death in the spinal cord.”
Moreover, p45 seems to have another role, that of promoting recovery.
On day 1 after SCI, all mice had a Basso Mouse Score (BMS) score of 0, indicating they were completely paraplegic. With time, Thy1-p45 transgenic mice exhibited weight-bearing postures and non-plantar stepping. ... locomotor performance following each time point was significantly better in Thy1-p45 transgenic mice compared to their WT [wild type, or non transgenic] littermates. These results demonstrate that over-expression of p45 promotes functional recovery following SCI.
"The great thing about P45 is that it can both inhibit the negative by blocking the conformational change that would lead to more cell death, while promoting the positive- the survival and growth of tissue- thus making it easier to foster recovery following spinal cord injury," Lee explains.
"If you can understand where you could tilt the balance of positive/negative signal, it would give you less damage while helping to promote healing," says Lee. "It could be combinatorial-maybe one molecule can do both, or maybe it's a combination of two molecules, one to negate, one to promote. The hope is if such a control switch could be found, more tissue could be preserved at the site of injury, thus increasing the chances that movement might someday be restored."
From the conclusion in the paper:
One major challenge in treating SCI is to develop strategies that can affect multiple signaling pathways simultaneously and synergistically. The multitude of concerted regulations by p45 makes it a powerful target for developing treatments for SCI. Understanding p45-mediated cellular and molecular mechanisms may provide insights into facilitating nerve regeneration in humans.
OK, could be promising as a therapy, certainly for acute SCI. Could p45 also have a role in a chronic model by assisting with the regenerative response? [Note: such speculation not addressed in the paper]. Meanwhile, proof of concept in a mouse is a long, long way from human use but the molecular biology of signaling is an area to follow, even if it’s from 50,000 feet above the technical detail.