Chemical connections between PLP and MS

I have a couple interesting articles about another possible cause of MS. In fact, one of these articles is what initially got me interested in proteolipid proteins’ role in MS for my senior seminar.

Here is the background story to the process. Myelin sheaths around the axons in vertebrates (ie humans) make nerve impulses go faster. These sheaths are achieved by fatty glial cells wrapping around the axon, or shaft, of the neuron. One type of myelinating glial cell is called an oligodendrocyte. It sends out a number of processes, each of which flattens out and wraps itself around an axon to form a segment of the myelin sheath. The tight wrapping is thought to be maintained by adhesion of several transmembrane proteins, including myelin basic protein (MBP) and proteolipid protein (PLP). PLP has been shown to have long chain fatty acids, namely palmitic acid side-chains.

I’ll admit that I cannot quite determine from the articles I’ve found, but I think these fatty acid chains act as a sort anchor for the proteins inside the membrane (I admit I’m making a leap here, I will look into this). These fatty acids are attached via thioesters on the cysteine residues. For those who aren’t up to speed on organic or biochemistry, cysteine is an amino acid with a thiol, or -S-H, side chain, and a thioester is an ester with a sulfur atom in place of oxygen between carbons. Loss of these fatty acids has been linked to decompaction of the rolled sheets (or lamellae) of the myelin sheet (Bizzozero et al, 2001). Decompaction of these sheets has been implicated in turn, with slowing velocity of nerve impulses (Gutierrez et al, 1995).

Dr. Sultan Darvesh researches Butyrylcholinesterase (BChE), a coenzyme with Acetylcholinesterase (AChE) found throughout the central nervous system. This enzyme has an affinity for deacylating thioesters attached to long-chain fatty acids. Knowing this, Darvesh looked at slides of brains from people with MS and people without MS. He found that BChE was expressed prominently in MS affected areas of the brain in MS patients. In normal brains, it was mostly only found in cholinergic pathways (Darvesh et al, 2010).

Darvesh worked on an experiment with a biochemist to test the deacylating affinities of BChE (Pottie et al, 2010). They developed a way to synthesize thioesters between cysteines and fatty acids of different lengths. They then introduced BChE in vitro (in a dish or test tube). With it they introduced a chemical called DTNB, a sulfur-bonded dimer. When a thioester was deacylated, the DTNB would split and one of the molecules would form a sulfur bridge with the protein analogue, leaving behind a yellow colored nitro thiophenolate, which allowed them to track the reaction. What they found was that the longer the fatty acid chain, the higher the affinity of the BChE for deacylating it.

It isn’t clear yet whether this activity is what happens in vivo, but this certainly could shed light on new MS pathways and possibly lead to new treatments involving BChE regulation. I also find it very interesting to study this condition from a chemical perspective.

Cited:

Bizzozero, OA, Bixler, HA, Davis, JD, Espinosa, A, and Messier, AM. Chemical deacylation reduces the adhesive properties of proteolipid protein and leads to decompaction of the myelin sheath J. Neurochem. 2001, 76: 1129-1141.

Darvesh, S, LeBlanc, AM, Macdonald, IR, Reid, GA, Bhan, V, Macaulay, RJ, Fisk, JD. Butyrylcholinesterase activity in multiple sclerosis neuropathology. Chem-Biol Interact. 2010, 187(1-3): 425-431.

Gutierrez, R, Boison, D, Heinemann, U, Stoffel, W. Decompaction of CNS myelin leads to a reduction of the conduction velocity of action potentials in optic nerve. Neurosci Lett. 1995, 195(2): 93-6.

Pottie, I.R.,  Higgins, E.A., Blackman, R.A., Macdonald, I.R., Martin, E., Darvesh, S. Cysteine Thioesters as Myelin Proteolipid Protein Analogues to Examine the Role of Butyrylcholinesterase in Myelin Decompaction. ACS Chem Neurosci. 2010, DOI 10.1021/cn100090g

 

Sorry for any articles where the full text is not available.

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1 Comment

  1. I encourage you to foster your interest in the chemical perspective. All else may be just so stories. We won’t know for sure until we do understand the chemistry.


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