J Neurol. 2010 May 12
Lee YC, Lin KP, Chang MH, Liao YC, Tsai CP, Liao KK, Soong BW.

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.

Abstract
Mutations in MPZ, which encodes myelin protein zero (P(0)), may lead to different subtypes of Charcot-Marie-Tooth disease (CMT). The aim of this study was to characterize the cellular manifestations of various MPZ mutations associated with CMT1, Dejerine-Sottas syndrome (DSS) and CMT2, and to correlate their cellular and clinical phenotypes.

Nine P(0) mutants associated with CMT1 (P(0)S63F, R98H, R277S, and S233fs), DSS (P(0) I30T and R98C), and CMT2 (P(0)S44F, D75V, and T124M), were investigated. Wild-type and mutant P(0) fused with fluorescent proteins were expressed in vitro to monitor their intracellular localization.

An adhesiveness assay was used to evaluate the adhesiveness of the transfected cells. Protein localization and cell adhesiveness of each mutant protein were compared and correlated with their clinical phenotypes.

Three different intracellular localization patterns of the mutant P(0) were observed. Wild-type P(0), P(0)I30T, S44F, S63F, D75V, T124M, and R227S were mostly localized on the cell membrane, P(0)R98H, and R98C were found in the endoplasmic reticulum (ER) or Golgi apparatus, and P(0)S233fs formed aggregates within the ER.

Cells expressing mutant P(0), as compared with those expressing wild-type P(0), demonstrated variable degrees of reduction in the cell adhesiveness.

The molecular patho-mechanisms of MPZ mutations are likely very complex and the clinical phenotype must be influenced by many genetic or environmental factors.

This complexity may contribute to the highly variable clinical manifestations resulting from different MPZ mutations.

My trusty sidekick Google alerted me to the following story of a boy with Dejerine-Sottas in England whose horseback riding program may be cut due to lack of funds and volunteers.

Michael Murphy, 13, has Dejerine-Sottas disorder, which affects the nervous system. He attends the centre every week instead of doing physical education lessons at his school in Mill Hill.
He has won a number of dressage awards and will be representing Great Britain at a dressage competition in Belgium next month.
His mother, Sue, said: “It would be terribly sad if the centre had to close on a Sunday as it really benefits the children and adults that come here.
“Parents are also encouraged by watching their children progress and I have been so happy to see my son not only enjoying himself here but also getting exercise to strengthen his core muscles.”

Knowing the way these things work (at least here in the States) I have to wonder if Michael took up horseback riding because his school doesn’t offer an adaptive physical education program and won’t accommodate him in a regular P.E. class. In any case, kudos to Michael for his achievements on horseback!
Full article after the jump.

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Myelin-making Schwann cells have an ability every aging Hollywood star would envy: they can become young again. According to a study appearing in the May 19 issue of the Journal of Cell Biology, David B. Parkinson (University College London, London, UK) and collogues have pinned down a protein that returns the cells to their youth, a finding that might help researchers understand why myelin production falters in some diseases.

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LOMA LINDA – Abbey Umali does not care if she comes in last place.
The 9-year-old girl is just happy to compete in the sixth annual PossAbilities Triathlon today at Loma Linda University.
Abbey – who has a rare form of muscular dystrophy – will compete against other able-bodied athletes in her age group.
“First, we run, then we bike, then we swim,” said Abbey, the Muscular Dystrophy Association’s 2008 National Goodwill Ambassador. “It’s really fun.”

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Nat Neurosci. 2007 Nov;10(11):1361-8.
Scholz J, Woolf CJ.
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.

Glia. 2008 Feb;56(3):306-17.
Developmental loss of NT-3 in vivo results in reduced levels of myelin-specific proteins, a reduced extent of myelination and increased apoptosis of Schwann cells.
Woolley AG, Tait KJ, Hurren BJ, Fisher L, Sheard PW, Duxson MJ.
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
This work investigates the role of NT-3 in peripheral myelination. Recent articles, based in vitro, propose that NT-3 acting through its high-affinity receptor TrkC may act to inhibit myelin formation by enhancing Schwann cell motility and/or migration. Here, we investigate this hypothesis in vivo by examining myelination formation in NT-3 mutant mice. On the day of birth, soon after the onset of myelination, axons showed normal ensheathment by Schwann cells, no change in the proportion of axons which had begun to myelinate, and no change in either myelin thickness or number of myelin lamellae. However in postnatal day 21 mice, when myelination is substantially complete, we observed an unexpected reduction in mRNA and protein levels for MAG and P(0), and in myelin thickness. This is the opposite result to that predicted from previous in vitro studies, where removal of an inhibitory NT-3 signal would have been expected to enhance myelination. These results suggest that, in vivo, the importance of NT-3 as a major support factor for Schwann cells (Meier et al., (1999) J Neurosci 19:3847-3859) over-rides its potential role as an myelin inhibitor, with the net effect that loss of NT-3 results in degradation of Schwann cell functions, including myelination. In support of this idea, Schwann cells of NT-3 null mutants showed increased expression of activated caspase-3. Finally, we observed significant reduction in width of the Schwann cell periaxonal collar in NT-3 mutant animals suggesting that loss of NT-3 and resulting reduction in MAG levels may alter signaling at the axon-glial interface.

A protein found in human hair shows promise for promoting the regeneration of nerve tissue and could lead to a new treatment option when nerves are cut or crushed from trauma.
In the current issue of Biomaterials, scientists from Wake Forest University School of Medicine reported that in animal studies the protein keratin was able to speed up nerve regeneration and improve nerve function compared to current treatment options.
“We found that the nerve repair happened more quickly and consistently, and that functional recovery was higher,” said Mark Van Dyke, Ph.D., senior author and an assistant professor of regenerative medicine. “The fact that we were able to accomplish this with gels made from keratin is pretty remarkable.”

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The New York Times recently digitized its pre-Internet archives and opened them to the public, so today I ran a search and found a single mention of Dejerine-Sottas disease. It’s an interesting article on the use of x-ray crystallography to shed some light on the proteins created by the P0 mutation, one of the mutations that causes Dejerine-Sottas.

Protein Linked to 3 Nerve Ailments

IN two papers representing the work of 19 researchers, scientists reported last week that they had seen, at a molecular level, the damage to an important protein that is the cause of three genetic nerve disorders. Dr. Thomas Bird, a professor at the University of Washington and chief of neurology at the Veterans Affairs hospital in Seattle, who is not associated with the groups who made the reports, said that the papers are examples of where medicine has arrived: at the molecular detail of human disease.

Read more of Protein Linked to 3 Nerve Ailments

A new Miami Institute for Human Genomics, which will search for genetic origins of common diseases such as autism and Alzheimer’s, opened its doors Tuesday to great expectations.
Its purpose: changing the way medicine works.
”The future of medicine depends entirely on projects from the field of genomics,” or the study of all the genes in humans, medical school dean Dr. Pascal Goldschmidt said at Tuesday’s opening.
The University of Miami institute is only the second of its kind in the United States. The Broad Institute of Harvard University and Massachusetts Institute of Technology was founded in 2003. Genomic research is part of the focus at Scripps Institute at Florida Atlantic University in Boca Raton, where 230 researchers are looking at discovering new drugs.
The UM genomics institute will focus on the genetic origins of multiple sclerosis, age-related macular degeneration, amyotrophic lateral sclerosis (Lou Gehrig’s disease), tuberculosis and Charcot-Marie-Tooth disease, as well as cardiovascular disease, neurodevelopmental disorders and cancer.
Read the rest of University of Miami center seeks diseases’ origins

Mol Pharm. 2007 Nov 14
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
Cytokine Research Laboratory and Pharmaceutical Development Center, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030
Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination.
To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life.
Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn’s disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.