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.


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.


Mimic Proteins on Viruses and Induction of Demyelination in Mice

I found an article on PubMed from a few years ago. Researchers engineered Theiler’s murine encephalomyelitisvirus (TMEV) to bear peptide epitopes naturally occurring in Haemophilius influenzae that mimics a sequence in the proteolipid protein (PLP) in the membrane the myelin. They found that mice infected with this virus carrying the epitope developed more of an immune response (i.e. an autoimmune response) than mice that were simply injected with the mimic peptides by themselves. What they also found was that the viruses could, in the authors’ words, exacerbate a preexisting, non-progressive autoimmune condition. The autoimmune response they were investigating in particular was the inflammation of the myelin in the Central Nervous System.

I found this very interesting, since this falls under the topic on which I want to do my senior seminar. The importance of this article is that the proteolipid protein is an important transmembrane protein in myelin, the sheath around the neurons, and it is important to myelin structure. Damage to the proteolipid proteins have been implicated in degradation of myelin, leading to multiple sclerosis. Multiple sclerosis has been linked to autoimmune responses and to viral infection.

In the experiment, exposure to a PLP sequence and to the mimic protein both resulted in an increased expression of MS or demyelination symptoms (lack of tail tone, impaired righting, varying degrees of hind-limb paralysis, etc.). They also resulted in the expression of higher concentrations of antibodies specific to PLP. This study strengthens evidence for a possible pathway of viral induction of MS.


Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis.

Croxford JL, Olson JK, Anger HA, Miller SD.

J Virol. 2005 Jul;79(13):8581-90.

Review of a Review: Mini Brains

This week the professor handed us a review article from the Royal Society about using insects as models for determining the cost-benefit relationship involved in learning and memory. As it explains, there is much evidence supporting a link between hippocampus size and learning in larger, more complex animals. But causation is not clear, and determining the size and neural density of such large brains is very difficult, because they are so large. The mushroom body, a higher processing center in insect brains, only tends to have a few hundred thousand neurons. Research into the costs of learning has expanded in the past decade with a lot of help from insects.

The brain is an expensive organ, taking up a lot of energy. One cost mentioned is the energy cost of maintaining resting potential. So, if learning is correlated to brain size and neural density, it is not necessarily adaptive. However, some insects perform surprisingly complex cognitive tasks. This may mean that more connections between neurons is better and more efficient than using more neurons. There is also evidence that higher order processing units may have at least as good an effect as upping the size of an entire brain. If we can learn the energy costs and performance of different units of nervous systems, we can understand how their relationship effected their evolution.

There is also an analysis of two basic types of costs of learning. Constitutive costs are costs that an animal pays whether or not it uses the memory. This can be a structure in the brain or even simply a lengthened axon resulting from a learning experience. There are also induced costs of learning. which are paid during the act of learning. There is a lot of evidence backing up the induced costs of learning, which may mean behavioral costs or the costs of processing information in the brain. Some studies on Drosophila have suggested that only crucial, repeated information makes it into the more costly type of memory storage. As well as encoding memory, deleting memory may be very expensive.

These studies have show gaps in that performance in a particular task does not necessarily translate into fitness. There is still a lot more to explore in this field.

Well, Aloha-loha There

Welcome to my new, and possibly short-lived blog. It only needs to last a semester. This is where I will be posting my thoughts on topics as required by my Neurobiology professor. This should be an interesting semester. Good luck, everyone.

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