NEW YORK (Reuters Health) - In a mouse model of Huntington disease (HD), oral administration of the non-toxic disaccharide trehalose inhibits the formation of truncated huntingtin protein aggregates, reduces HD brain pathology, improves motor function, and significantly extends life, according to Japanese researchers.
These results “make trehalose promising as a therapeutic drug or lead compound” for the treatment of Huntington disease and other polyglutamine diseases, Dr. Nobuyuki Nukina and colleagues from the RIKEN Brain Science Institute in Saitama write in the January 18th online edition of Nature Medicine.
There is considerable evidence tying polyglutamine-mediated aggregation of insoluble huntingtin protein to Huntington disease (See related Reuters Health report Jan. 22, 2003). Dr. Nukina’s team found through in vitro screening studies that a number of disaccharides inhibit this aggregation. “Trehalose has the strongest effect,” he told Reuters Health.
In a mouse model of Huntington disease, animals spontaneously ingesting 2% trehalose in drinking water had substantially fewer huntingtin protein aggregates in the cerebrum and liver, better motor dysfunction, and lived significantly longer than untreated animals. Although trehalose appears to prevent the formation of new aggregates, it does not appear to reverse pathology.
Results of cellular studies suggest that the beneficial effects of trehalose lie in its ability to bind to expanded polyglutamines and stabilize the partially unfolded polyglutamine-containing protein.
“The protection of aggregation formation is important to block the disease cascade and stabilize the polyglutamine-bearing molecule, which is destabilized by polyglutamine expansion,” Dr. Nukina explained.
Trehalose, which is metabolized to glucose, did not alter fasting blood glucose in the animals, which is important the researchers note, given that individuals with Huntington disease are prone to diabetes.
“It is necessary to evaluate the effectiveness, dose and safety of trehalose in human trials,” Dr. Nukina concluded, pointing out that trehalose may also have therapeutic potential against other neurological disorders caused by aggregation of proteins with polyglutamine repeats such as Alzheimer disease, Parkinson disease, prion disease, and amyotrophic lateral sclerosis
Source: Nat Med 2004.DOI:10.1038/nm985. [ Google search on this article ]
Copyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
