Linking Nobel Prize to SCI Research

Posted by Sam Maddox in Research News on October 04, 2016

The Nobel Prize in Physiology or Medicine was awarded this week to Japanese scientist Yoshinori Ohsumi of the Tokyo Institute of Technology for discovering how autophagy works. Autophagy, from its Greek roots, means self-eat, or in biology, the ability of a cell to cannibalize itself by recycling its contents.

There will have been numerous articles about Ohsumi and this work. Start here, with the official announcement from the Nobel Prize site. The primary work, using yeast cells, dates to the early 1990s. This, from the announcement, sets up our coverage:

Thanks to Ohsumi and others following in his footsteps, we now know that autophagy controls important physiological functions where cellular components need to be degraded and recycled. Autophagy can rapidly provide fuel for energy and building blocks for renewal of cellular components, and is therefore essential for the cellular response to starvation and other types of stress.

In interviews, Ohsumi has emphasized the importance of basic science; he never set out to find medical treatments. There is much excitement about helping people with diabetes, Alzheimer’s, cancer, and all sorts of neurological issues, but that’s all very recent. Ohsumi says his work was just basic biology, and that sort of nuts and bolts investigation must continue. “Still we have so many questions,” he said. “Even now we have more questions than when I started.”

To the point for a blog about spinal cord injury research: Autophagy is important in the process of repair or regeneration of damaged nerve cells. Here’s a paper, for example, that came out two weeks ago from a group of Chinese researchers: “Autophagy induction stabilizes microtubules and promotes axon regeneration after spinal cord injury.”

They admit they don’t know for sure how this cellular Pac-Man process plays out in regeneration but present evidence that autophagy maintains cellular balance, or homoeostasis, by degradation of certain cellular components. They found a peptide that could switch on autophagy. When they did that, axons were better able to remodel the structural components of their cell bodies (cytoskeletons) to regenerate. The mice improved function. From the paper:

Remodeling of cytoskeleton structures, such as microtubule assembly, is believed to be crucial for growth cone initiation and regrowth of injured axons. Autophagy plays important roles in maintaining cellular homoeostasis, and its dysfunction causes neuronal degeneration.

We found that autophagy induction promoted neurite outgrowth, attenuated the inhibitory effects of nonpermissive substrate myelin, and decreased the formation of retraction bulbs following axonal injury in cultured cortical neurons. Interestingly, autophagy induction stabilized microtubules by degrading SCG10, a microtubule disassembly protein in neurons. In mice with spinal cord injury, local administration of a specific autophagy-inducing peptide, Tat-beclin1, to lesion sites markedly attenuated axonal retraction of spinal dorsal column axons and cortical spinal tract and promoted regeneration of descending axons following long-term observation. Finally, administration of Tat-beclin1 improved the recovery of motor behaviors of injured mice.

Clinical relevance? Could be.

This study reveals a critical role of autophagy in stabilizing neuronal microtubules and a promising therapeutic effect of an autophagy-inducing reagent on CNS axons following injury.

Another Chinese group published a paper last month reporting that a common diabetes drug called Metformin increases autophagy in a spinal cord animal model while decreasing inflammation and a form of programmed cell death called apoptosis. This results in a neuroprotective effect and therefore a reduction of SCI damage.

In another Chinese laboratory, it was reported that Atorvastatin, aka Lipitor, is also neuroprotective in SCI. The drug appears to bump up autophagy and also improves recovery.

Many labs all over the world are looking ways to modify cell growth machinery, including the autophagy process. Here’s an example: Valproic acid bumps up autophagy and is said to improve SCI.

You may recall our coverage a couple of months ago of the very cool molecule called rapamycin, which is an immunosuppressant with great therapeutic potential to reduce the development of neuropathic pain following spinal cord injury, and which has been reported to reduce nerve tissue damage and improve recovery after SCI in mice.

Turns out rapamycin reportedly promotes autophagy in animal models, is neuroprotective, and improves outcome.

OK, we’ve been turning autophagy up. What about down? A group in Italy reported in August that autophagy has a flip side, as do many functions of the immune system. Inhibiting autophagy in a spinal cord injury model, they note, seems to improve survival of a certain type of nerve cell (rubrospinal neurons, which are responsible for voluntary motor function). “Thus,” say the authors, “autophagy is a promising target for the development of therapeutic interventions in the treatment of SCIs.”

Last April another Chinese group published a paper that also suggests that autophagy can be detrimental. Reduce the urge to self-eat and save spinal function. The title tells their story: “Inhibition of Autophagy by Estradiol Promotes Locomotor Recovery after Spinal Cord Injury in Rats.”

The volume of work in autophagy is prodigious, but of course, as our Nobel laureate has said, there is more ahead. Autophagy has been shown to be another key component of regeneration, and it is being figured out. Congratulations to Professor Ohsumi for lighting the way.

The National Paralysis Resource Center website is supported by the Administration for Community Living (ACL), U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling $8,700,000 with 100 percent funding by ACL/HHS. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by ACL/HHS, or the U.S. Government.