Author Topic: More Huntington’s Research More Evidence for Trehalose  (Read 3827 times)

Offline JC Spencer

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More Huntington’s Research More Evidence for Trehalose
« Reply #1 on: January 02, 2010, 07:59:09 PM »
by J. C. Spencer

Researcher at UCLA discover that a molecular switch prevents Huntington’s Disease from advancing.  A subtle modification of only two amino acids in a large protein can prevent the onset of HD.  Research evidence is mounting that sugars are responsible for helping fold the proteins.   When the proteins are not folded properly various neurodegenerative diseases take over the body.  Earlier I reported on how Trehalose alleviates polyglutamine-mediated pathology in mouse model of Huntington disease. That article is at the end of this report.

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Los Angeles Time - Health Section
January 1, 2010

Rodent of the Week: A new lead on Huntington's disease

There's no cure or treatment for Huntington's disease, one of the most devastating genetic disorders. But a study in animals suggests a possible new approach to someday treating the disorder.

Researchers at UCLA have identified a molecular switch that prevents the disease from developing in mice. The study was published last week in the journal Neuron.

Huntington's disease causes progressive neurological damage. Symptoms first appear in mid-life and gradually rob patients of their ability to talk, walk, think or even swallow. The disease is caused by an inherited mutation in the polyglutamine region of a protein called huntingtin. In a first phase of research, scientists at UC Irvine showed that two amino acids near the beginning of the huntingtin protein can be altered by a chemical process called phosphorylation. The UCLA researchers then tested whether phosphorylation could influence the disease process. Using two mouse models with the Huntington's disease mutation, they modified the two amino acids in different ways -- one to mimic phosphorylation and one to prevent it.

They found that preventing phosphorylation caused the mice to develop symptoms of the disease but mimicking it did not. Similar research, performed at the University of Pittsburgh, has also shown that mimicking phosphorylation of a fragment of the huntingtin gene reduces the protein's tendency to form clumps.

"We were surprised to find that subtle modification of only two amino acids in this very large protein can prevent the onset of disease," the lead author of the study, X. William Yang, said in a news release.

-- Shari Roan
Photo credit: Advanced Cell Technology Inc.

http://latimesblogs.latimes.com/booster_shots/2010/01/huntingtons-disease.html

www.endowmentmed.org

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Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD Mice

Xiaofeng Gu1, 2, 3, Erin R. Greiner1, 4, Rakesh Mishra5, Ravindra Kodali5, Alex Osmand6, Steven Finkbeiner7, Joan S. Steffan8, Leslie Michels Thompson8, 9, 10, Ronald Wetzel5 and X. William Yang1, 2, 3

1 Center for Neurobehavioral Genetics, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
2 Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
3 Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA
4 Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
5 Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
6 Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA
7 Gladstone Institute of Neurological Disease, Taube-Koret Center for Huntington's Disease Research, Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
8 Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92697, USA9 Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697, USA
10 Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA

Summary

The N-terminal 17 amino acids of huntingtin (NT17) can be phosphorylated on serines 13 and 16; however, the significance of these modifications in Huntington's disease pathogenesis remains unknown. In this study, we developed BAC transgenic mice expressing full-length mutant huntingtin (fl-mhtt) with serines 13 and 16 mutated to either aspartate (phosphomimetic or SD) or alanine (phosphoresistant or SA). Both mutant proteins preserve the essential function of huntingtin in rescuing knockout mouse phenotypes. However, fl-mhtt-induced disease pathogenesis, including motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration are abolished in SD but preserved in SA mice. Moreover, modification of these serines in expanded repeat huntingtin peptides modulates aggregation and amyloid fibril formation in vitro. Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in vivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy.

http://www.cell.com/neuron/abstract/S0896-6273(09)00936-2

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Trehalose alleviates polyglutamine-mediated pathology in mouse model of Huntington disease

Nat Med. 2004 Feb;10(2):123-4.

Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M,
Nukina N. Laboratory for Structural Neuropathology, RIKEN Brain Science
Institute, 2-1 Hirosawa, Wako City, Saitama 351-0198, Japan.

Abstract:

Inhibition of polyglutamine-induced protein aggregation could provide treatment
options for polyglutamine diseases such as Huntington disease. Here we showed
through in vitro screening studies that various disaccharides can inhibit
polyglutamine-mediated protein aggregation. We also found that various
disaccharides reduced polyglutamine aggregates and increased survival in a cellular
model of Huntington disease. Oral administration of trehalose, the most effective of
these disaccharides, decreased polyglutamine aggregates in cerebrum and liver,improved motor dysfunction and extended lifespan in a transgenic mouse model of
Huntington disease. We suggest that these beneficial effects are the result of
trehalose binding to expanded polyglutamines and stabilizing the partially unfolded
polyglutamine-containing protein. Lack of toxicity and high solubility, coupled with
efficacy upon oral administration, make trehalose promising as a therapeutic drug
or lead compound for the treatment of polyglutamine diseases. The saccharidepolyglutamine
interaction identified here thus provides a new therapeutic strategy for
polyglutamine diseases.

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