Here’s a paper released this week about an enzyme that may be related to multiple sclerosis. The work, from the Mayo Clinic, was supported by Reeve Foundation grants. Science Daily picked up the news item: “Halting an Enzyme Can Slow Multiple Sclerosis in Mice.” The coverage is based on a publication in Brain Pathology: “Kallikrein 6 Regulates Early CNS Demyelination in a Viral Model of Multiple Sclerosis.”
“We were able to slow the course of disease through early chronic stages, both in the brain and spinal cord," said lead author Isobel Scarisbrick, Ph.D. Others on the team include Hyesook Yoon, Michael Panos, Nadya Larson, Sachiko I. Blaber, Michael Blaber and Moses Rodriguez.
This research, indeed, appears to offer promise in treating MS: in this animal model, getting rid of the Kaillikrein 6 enzyme with an antibody improved the course of the disease:
The Kallikrein 6 neutralizing antibody had reduced inflammatory white blood cells and slowed the depletion of myelin basic protein, a key component of the myelin sheath.
There’s a lot of work to do to make an antibody to the exact enzyme linked to neuron damage and cell death in MS. What the Mayo studies are about, in broader terms, are the biochemical signals that cause nerve disease. K 6 appears to be turned up at sites of nerve injury by infiltrating immune and local CNS cells. Understanding what signals activate this process might also explain what goes wrong the minutes and even days after nerve trauma.
To be sure, there are many things happening in the secondary layer of trauma, some good, many bad. The immune system tries to clean up the chaos. But there is inflammation, blood loss and a variety of toxic molecular events, including reactive astrogliosis -- the response to trauma or disease by neural support cells called astrocytes. Trauma renders these cells “reactive,” and that can lead to axon-blocking scar formation. The astrocytes and scarring story has been around for 100 years. What’s coming to light now is that astrogliosis is much more nuanced than just scar; it appears that reactive astrocytes also protect CNS cells and tissue in various ways.
What’s caught the attention of the neuro disease and trauma field – and why this Mayo Clinic research becomes of interest to the spinal cord community (and the main reason Reeve provided funding) – is the role K family enzymes (there are 15) play in astrogliosis. The Mayo group has already shown that K 1 is related to MS and that K 6 is elevated in spinal cord injury; it’s also upregulated in animal models of stroke and in patients with post-polio syndrome. .
Scarisbrick and her team have been working on the K enzymes for more than a decade. Here
’s an older but not too dated video of Scarisbrick describing the science.
The MS hypothesis, from 2008: “Kallikreins are Associated with Secondary Progressive Multiple Sclerosis and Promote Neurodegeneration
.” This one includes K 1: These enzymes “may serve as serological [in the blood] markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death.”
Here is the SCI link, from 2006: “Dynamic Role of Kallikrein 6 in Traumatic Spinal Cord Injury
.” Says the paper: “K 6 enzymatic cascades mediate events secondary to spinal cord trauma, including dynamic modification of the capacity for axon outgrowth.”
Just days ago, the Scarisbrick group also just published this: “Kallikrein 6 is a Novel Molecular Trigger of Reactive Astrogliosis
.” This was also supported in part with Reeve Foundation funds. From the paper: “These studies indicate that K 6 is positioned to serve as a molecular trigger of select physiological processes involved in the development of astrogliosis…”
It's important to discover triggers and molecular signal sources. That means scientists will most likely build antibodies or other drugs to control the processes, switching signals on or off as needed. The K enzyme story is fairly new in the scheme of things. It’s not the answer to MS, though it suggests an interesting treatment possibility. The enzyme is a piece of an enormously complex system of signals and responses; many labs are working to unravel this sublimely difficult biology.