New drug 'dials down' protein synthesis to treat demyelinating diseases

April 22, 2015 by Ellen Goldbaum, University at Buffalo
Structure of a typical neuron. Credit:

In 2013, University at Buffalo researchers published a paper showing how slowing down protein synthesis can improve myelin production and repair in some demyelinating diseases, such as Charcot-Marie-Tooth disease, (CMT). The research held promise for other misfolded protein diseases, such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS).

The drawback was that the small molecule that slowed protein synthesis had side effects rendering it unsuitable for human use.

At the time, the UB researchers, led by Lawrence Wrabetz, MD, director of UB's Hunter James Kelly Research Institute, noted that if they could find a new version of the agent they used that was safe and effective, it could lead to new therapeutic strategies for CMT

Earlier this month, Wrabetz and others co-authored a paper in the journal Science that does just that. The lead author is Anne Bertolotti, program leader in the Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK.

In preclinical trials in animals, the Science paper reports, a new candidate drug called Sephin1 can markedly improve CMT and familial (ALS), two diseases of proteostasis (protein homeostasis, the process keeping protein production in balance in cells).

While the diseases are otherwise unrelated, both can result from difficulties in protein folding. In the case of ALS, the misfolded proteins are toxic to neurons and kill them, whereas in CMT neuropathy, the misfolded proteins disturb the production of myelin, the crucial fatty material that normally wraps the axons of neurons, allowing them to signal effectively.

"Our 2013 study and others have found that in diseases caused by proteostasis, keeping protein production more stringently and persistently dialed down is good for limiting disease," said Wrabetz, also professor of neurology and biochemistry in UB's School of Medicine and Biomedical Sciences. "Professor Bertolotti and her colleagues at Cambridge modified a molecule they discovered in 2011 in order to provide a candidate drug that regulates but without the toxic side effects."

Basing the design of the preclinical trial on the same one they published in 2013, Wrabetz and his colleague, Maurizio D'Antonio at San Raffaele Scientific Institute in Milan, joined by Indrajit Das of Cambridge, treated juvenile animals with CMT with Sephin1. After five months of treatment, the results were unequivocally positive.

"Motor function in the animals returned to normal, the amount of myelin destruction was reduced by 70 percent and myelin thickness improved remarkably," said Wrabetz.

There were equally positive results when Das treated the familial ALS model with Sephin1 at Cambridge.

Sephin1 regulates a key factor in , and does so by maintaining phosphorylation, or the addition of a phosphate group.

"The finding is important because proteostasis diseases are multiple and affect many people," said Wrabetz, noting that they include neurodegenerative conditions, such as Alzheimer's and Parkinson's, such as multiple sclerosis and certain types of cancers and some subtypes of diabetes.

"It's important to emphasize that further studies are necessary to confirm that the effects in these two animal models will translate to patients with CMT and familial ALS and then, that this candidate drug or similar drugs could be useful in other diseases where proteostasis is a factor," Wrabetz explained. "Nonetheless, this study is an important first step toward developing a therapeutic strategy for these diseases with a candidate drug that could potentially be used in clinical trials."

Wrabetz and Laura Feltri, MD, UB professor of biochemistry and neurology, are also interested in exploring the study's relevance to leukodystrophies, the rare and severe developmental diseases of myelin in the brain and nerves. He noted that imbalances in proteostasis have been reported to contribute to some leukodystrophies.

Currently they are exploring whether altered proteostasis is present in animal models of Krabbe leukodystrophy, the disease that afflicted Hunter James Kelly, for which the Hunter James Kelly Research Institute is named.

Explore further: Hitting 'reset' in protein synthesis restores myelination, suggests new treatment for misfolded protein diseases

More information: "Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit." Science 10 April 2015: Vol. 348 no. 6231 pp. 239-242 DOI: 10.1126/science.aaa4484

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1 / 5 (1) Apr 22, 2015
The link from nutrient-dependent RNA-directed DNA methylation and RNA-mediated amino acid substitutions to cell type differentiation is not clear.

Journal article excerpt: "Sephin1 specifically bound a recombinant fragment of PPP1R15A (amino acids 325 to 636) but not the highly related PPP1R15B (amino acids 340 to 698)..."

It might help evolutionary theorists to understand the significance of RNA-mediated events compared to mutations if discussion of alternative splicings and chromatin remodeling during life history transitions was included in the context of nutrient-dependent top-down causation and phosphorylation that is required to link amino acid substitutions and thermodynamic cycles of protein biosynthesis and degradation to organism-level thermoregulation in species from microbes to man.

Many theorists seem willing to accept the pseudoscientific nonsense about mutations and evolution, but unwilling to accept the facts about cell type differentiation.
1 / 5 (1) Apr 22, 2015
See for a 5.5 minute review of cell type differentiation: Nutrient-dependent / Pheromone-controlled thermodynamics and thermoregulation

See also: http://www.biomed...4/14/666 Excerpt: "Our identification of GO categories related to protein phosphorylation that were enriched for genes with methylated splice junctions is consistent with a similar finding in a recent study of species-specific alternative exons [45]. The authors present evidence that argues that alternative splicing is used to alter protein phosphorylation, which can alter protein stability, subcellular localization, activity, and other properties [45]."
1 / 5 (2) Apr 22, 2015
Hey, JVK, we already know you're a creationist.
1 / 5 (1) Apr 22, 2015
Dobzhansky was a creationist.His work from 1973 was included in the recent review: "Combating Evolution to Fight Disease" http://www.scienc...88.short

Does anyone want to separate his creationist views from their ridiculous theories? The issue here is the role of amino acid substitutions and fixation by phosphorylation. The reason that topic is addressed by serious scientists is that they want to encourage others to learn more about biologically-based cause and effect in all species.

See: MSX3 Switches Microglia Polarization and Protects from Inflammation-Induced Demyelination

AND Dobzhansky (1973) http://www.jstor..../4444260 "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla" (p. 127). -- unless you are a biologically uninformed science idiot.

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