Linked Life Data

15759103

Source:http://linkedlifedata.com/resource/pubmed/id/15759103

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-5-5
pubmed:abstractText
Polyglutamine diseases, such as Huntington disease (HD) and spinocerebellar ataxia 1 and 3, are autosomal dominant neurodegenerative disorders. They are caused by CAG trinucleotide repeat expansions that are translated into abnormally long polyglutamine tracts. One of the pathological hallmarks in polyglutamine diseases is the formation of intranuclear inclusions of polyglutamine-containing proteins in the brain. Although causal relationships between polyglutamine aggregation and cellular toxicity are much debated, inhibition of the polyglutamine-mediated protein aggregation may provide treatment options for polyglutamine diseases. However, the extreme insolubility of expanded polyglutamines makes it difficult to prepare polyglutamine-containing proteins on a large scale and to search for aggregation inhibitors by in vitro high-throughput screening. To overcome this we developed a novel in vitro model system for polyglutamine diseases using myoglobin as a host protein. We searched for small molecules that inhibit polyglutamine-mediated aggregation by in vitro screening with a mutant myoglobin containing a 35 polyglutamine repeat. The screening assay revealed that disaccharides have a potential to inhibit polyglutamine-induced protein aggregation and to increase survival in a cellular model of HD. Oral administration of trehalose, the most effective disaccharide in vitro, decreased polyglutamine aggregates in the cerebrum and liver, improved motor dysfunction and extended life span in a transgenic mouse model of HD. In vitro experiments suggest that the beneficial effects of trehalose result from its ability to bind and stabilize polyglutamine-containing proteins. The lack of toxicity and high solubility, coupled with its efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment of polyglutamine diseases. The stabilization of aggregation-prone proteins with small molecules is an attractive strategy because it can block the initial stage of the disease cascade. In addition, this therapeutic approach could be applied not only to polyglutamine diseases but also to a wide variety of misfolding-induced diseases.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0946-2716
pubmed:author
pubmed:issnType
Print
pubmed:volume
83
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
343-52
pubmed:dateRevised
2011-7-8
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
A novel therapeutic strategy for polyglutamine diseases by stabilizing aggregation-prone proteins with small molecules.
pubmed:affiliation
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-city, 351-0198 Saitama, Japan. motomasa@cmp.ucsf.edu
pubmed:publicationType
Journal Article, Review, Research Support, Non-U.S. Gov't