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Structure and Stability of Internodal Myelin in Mouse Models of Hereditary Neuropathy

October 30, 2005

Filed under: Journal articles

Journal of Neuropathology & Experimental Neurology. 64(11):976-990, November 2005.
Avila, Robin L BS; Inouye, Hideyo PhD; Baek, Rena C BS; Yin, Xinghua MD; Trapp, Bruce D PhD; Feltri, M Laura MD; Wrabetz, Lawrence MD; Kirschner, Daniel A PhD
Peripheral neuropathies often result in abnormalities in the structure of internodal myelin, including changes in period and membrane packing, as observed by electron microscopy (EM). Mutations in the gene that encodes the major adhesive structural protein of internodal myelin in the peripheral nervous system of humans and mice-P0 glycoprotein-correlate with these defects. The mechanisms by which P0 mutations interfere with myelin packing and stability are not well understood and cannot be provided by EM studies that give static and qualitative information on fixed material. To gain insights into the pathogenesis of mutant P0, we used x-ray diffraction, which can detect more subtle and dynamic changes in native myelin, to investigate myelin structure in sciatic nerves from murine models of hereditary neuropathies. We used mice with disruption of one or both copies of the P0 gene (models of Charcot-Marie-Tooth-like neuropathy [CMT1B] or Dejerine-Sottas-like neuropathy) and mice with a CMT1B resulting from a transgene encoding P0 with an amino terminal myc-tag. To directly test the structural role of P0, we also examined a mouse that expresses P0 instead of proteolipid protein in central nervous system myelin. To link our findings on unfixed nerves with EM results, we analyzed x-ray patterns from unembedded, aldehyde-fixed nerves and from plastic-embedded nerves. From the x-ray patterns recorded from whole nerves, we assessed the amount of myelin and its quality (i.e. relative thickness and regularity). Among sciatic nerves having different levels of P0, we found that unfixed nerves and, to a lesser extent, fixed but unembedded nerves gave diffraction patterns of sufficient quality to distinguish periods, sometimes differing by a few A. Certain packing abnormalities were preserved qualitatively by aldehyde fixation, and the relative amount and structural integrity of myelin among nerves could be distinguished. Measurements from the same nerve over time showed that the amount of P0 affected myelin’s stability against swelling, thus directly supporting the hypothesis that packing defects underlie instability in “live” or intact myelin. Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies. [Read more]

Curcumin Treatment Abrogates Endoplasmic Reticulum Retention and Aggregation-Induced Apoptosis Associated with Neuropathy-Causing Myelin Protein Zero-Truncating Mutants

October 29, 2005

Filed under: Journal articles

Mehrdad Khajavi, Ken Inoue, Wojciech Wiszniewski, Tomoko Ohyama, G. Jackson Snipes, and James R. Lupski
The American Journal of Human Genetics, volume 77 (2005), pages 841–850
Mutations in MPZ, the gene encoding myelin protein zero (MPZ), the major protein constituent of peripheral myelin, can cause the adult-onset, inherited neuropathy Charcot-Marie-Tooth disease, as well as the more severe, childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3 end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. We examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and we found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. Curcumin, a chemical compound derived from the curry spice tumeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. Our findings suggest that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and may potentially have a therapeutic role in treating selected forms of inherited peripheral neuropathies. [Read more]

New insights into how genetic mutations arise

Filed under: Genetics

Researchers at Stanford University have created a larger-than-normal DNA molecule that is copied almost as efficiently as natural DNA.
The findings, reported in the Oct. 25 online edition of the Proceedings of the National Academy of Sciences (PNAS), may reveal new insights into how genetic mutations-tiny mistakes that occur during DNA replication-arise. The discovery was made in the laboratory of Eric Kool, a professor of chemistry at Stanford and co-author of the PNAS study. [Read more]

Booklet is ready and more news from HNF – October 2005

October 28, 2005

Filed under: Search for a Cure

The following is from the Hereditary Neuropathy Foundation‘s October newsletter:
We’re pleased to announce that our patient information booklet is now available for distribution to our registered HNF members. This high-quality production presents an in depth overview of the common experiences of coping with CMT. This essential guide is provided to HNF members along with full access privileges to For members who have registered and provided a membership donation, we thank you and hope you will find our booklet of assistance.
Be sure and register at and read our latest research article to learn how researchers from Howard Hughes Medical Institute are using muscle tissue from tarantulas to understand the detailed structure and arrangement of molecular motor control; a key component needed to better understand the progressive nature of CMT.
Our public awareness motto is “leave NO stone unturned” and we’ve been busy turning over stone after stone, all the way to Capital Hill! In the past few months we’ve met with government officials in Washington D.C.; presented at the American Academy of Neurology, in Atlanta, Georgia; and promoted our children’s book at the world renowned New York Book Expo.
Jump on board… if you’d like us to forward our patient information booklet to your family physician or neurologist, simply provide us their contact information through our email at: This courtesy is available to HNF members nation wide.
As you approach the holiday season be sure and pace your energy and check out the special gift giving items available through iGive. Why shop til you drop when you can conveniently click your way through the stores… while at the same time support up and coming projects, all geared to improve the quality of life of people with CMT. And by the way; did you know there is an official CMT postage stamp now available? Just imagine – your snail mail can help LICK CMT as all sales proceeds will be directed to research slotted for 2006.
In the meantime, we wish you and your family a safe and enjoyable celebration this Thanksgiving!
Susan Wheeler, Executive Director
Allison Moore, President

Researchers Find Protein Determines Nerve’s Fate

October 26, 2005

Researchers at the Skirball Institute of Biomolecular Medicine, New York University (NYU) School of Medicine, have found that a protein (neuregulin-1 type III, or NRG1-III) essential for the protective wrapping around a nerve’s central wiring, or axons, also determines its fate.
Just as plastic coatings insulate electrical wires, myelin coats nerve fibers. This fatty substance also accelerates message-carrying impulses that travel along the nerve fibers and frees them from interference. For more than a decade, scientists have known that nerve cells make neuregulins, growth proteins that promote glial cell growth. However, the delicate interaction between nerve cells and the glial cells (Schwann cells) that produce them remain a mystery.
It has been shown that growth factor protein NRG1-III triggers glial cells to make myelin. This knowledge should lead researchers to develop more effective treatments for several neurological diseases, including peripheral neuropathy. [Read more]

Local anesthetics are effective for neuropathic pain

October 25, 2005

Filed under: Neuropathic Pain Management

Lidocaine and similar local anesthetics are effective for treating pain that emanates from damaged nerves, according to a systematic review of current evidence.
Neuropathic pain, which can occur with chronic diseases or conditions, is frequently unresponsive to treatment and worsens over time.
“Intravenous lidocaine and oral derivatives relieve pain from damage to the nervous system,” found authors Ivo W. Tremont-Lukats, M.D., of the M.D. Anderson Cancer Center in Houston, and colleagues. They add that the drugs, “were safe in controlled clinical trials for neuropathic pain, were better than placebo and were as effective as other analgesics.” [Read more]