Jerry Silver: Breaking through the CSPG Roadblock

This is my second year and I’m so happy to be here — this is one of the most important foundations in the country.  I’m doing two talks, one today and one tomorrow, and I’ll do more if you want.

He’s showing his Cajal-drawn image of SCI lesions in cat dorsal columns with the stunted axons . . . there’s the problem: how do you wake up those sleeping axons?

People have speculated for years about what goes wrong.  Extrinsic barriers, intrinsic barriers, inhibitory molecules, or maybe something weird like a welcoming environment, sort of like a beach chair — an environment that makes the axon so happy that it’s basically just sitting there enjoying life.

He’s got a little cartoon slide up, which he says he made 25 years ago, having no idea that the beach chair idea was going to turn out to be the right one.

Proteoglycans are nature’s barriers.  They’re all over the place for good reasons, but unfortunately they’re also in the lesion, especially in the center of the lesion, less and less so as you go out from it.

Years ago they transplanted fully adult sensory neurons into the white matter where they should have been able to grow like crazy.  What happened instead is that when they got to the lesion, they went into it and settled down for a nice long visit.  At very chronic injuries, they grow the same way, only not as robustly.

The adult cord allows growth, everywhere except right in the lesion.  Showing a film of adult dorsal root ganglion neurons growing . . . and then trying to grow in the lesion but turning away as if repelled.  So what’s the inhibitory juice?  Well . . . that’s the sugars.  Keeping in mind that the beach chairs are clustered together in the middle of the lesion.

Jesus, showing the end of axon trying like hell to grow.  Its tip is just bubbling away, can’t grow, can’t go back, just swirling, stuck in a proteoglycan, enjoying life on a beach chair.

Who’s the beach chair?  Your own oligodendrocyte progenitor cells — OPCs . . . how do we get rid of them?  We’ve found the first receptor (the thing that let’s cells signal) that binds proteoglycan.  It’s an enzyme that creates strong adhesion . . . they’re what’s known as LAR family receptors.  They bind to sugars.

They know about two receptors; one is Sigma one is LAR.  What happens is that a gyrating growth cone calls to them.  Receptor off = less adhesion and more growth.  Receptor on = more adhesion and less growth.

There’s also a thing called a wedge domain; they designed two of them, one each for LAR and Sigma.  The idea was to throw these wedges in and see if they could unstick the receptors — turn them off, so to speak.

The only thing so far that has ever allowed nerves to cross the injury spot is ChABC — Chondroitinase.  These wedges work better, because they fool the receptors about the nature of their environment.  Lordy.  It’s also true that you must find the exact right dosage and combination of these wedges . . .

Okay, all that was in vitro stuff . . . how about in a rodent.  A rodent with a T injury.  A double blind experiment.  Paralyzed animals.  Severely handicapped.  Both wedges, no help.  One of them alone works very, very well for almost half the animals.

There it is . . the rat walking.  Also, rats pee. Injured rats can still pee a little, unlike humans.  Some of the treated rats improved to normal, some didn’t . . .

Why?  Almost all the animals improved, but not in everything.  Some got grid walking, some got urination, some got BBB scores, and some got all three.

The key is to inactivate the PTP Sigma to release entrapment of neurons and allow for motile growth cones.  A daily subcutaneous injection . . .

Chronics????  They’re working out optimal doses for acute injuries . . . and chronics is what he’s going to talk about tomorrow.

Yikes.

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3 Comments on “Jerry Silver: Breaking through the CSPG Roadblock”

  1. mld Says:

    http://en.wikipedia.org/wiki/Proteoglycans

    “Function

    Proteoglycans are a major component of the animal extracellular matrix, the “filler” substance existing between cells in an organism. Here they form large complexes, both to other proteoglycans, to hyaluronan and to fibrous matrix proteins (such as collagen). They are also involved in binding cations (such as sodium, potassium and calcium) and water, and also regulating the movement of molecules through the matrix. Evidence also shows they can affect the activity and stability of proteins and signalling molecules within the matrix. Individual functions of proteoglycans can be attributed to either the protein core or the attached GAG chain and serve as lubricants.”

  2. katewill Says:

    Thank you!


  3. […] in the blog anywhere, but there was a moment on the first day after Jerry Silver talked about removing the CSPG roadblocks when he told me that today was just the warm-up . . . he was going to talk about […]


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