Linked Life Data

11912178

Source:http://linkedlifedata.com/resource/pubmed/id/11912178

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2002-3-25
pubmed:abstractText
In Huntington's disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older Hdh(Q111) knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, two proteins shown to reduce inclusions and glutamine toxicity in other HD models. Thus, potential HD therapies in man might be directed at different levels: preventing the disease-initiating mechanism or slowing the subsequent progression of pathogenesis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0964-6906
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
633-40
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:11912178-Animals, pubmed-meshheading:11912178-Caspase 1, pubmed-meshheading:11912178-Cell Nucleus, pubmed-meshheading:11912178-Corpus Striatum, pubmed-meshheading:11912178-Gait, pubmed-meshheading:11912178-Genes, Dominant, pubmed-meshheading:11912178-Glutamine, pubmed-meshheading:11912178-Huntington Disease, pubmed-meshheading:11912178-Immunologic Factors, pubmed-meshheading:11912178-Mice, pubmed-meshheading:11912178-Mice, Knockout, pubmed-meshheading:11912178-Mice, Transgenic, pubmed-meshheading:11912178-Mutagenesis, Insertional, pubmed-meshheading:11912178-Nerve Tissue Proteins, pubmed-meshheading:11912178-Neurodegenerative Diseases, pubmed-meshheading:11912178-Nuclear Proteins, pubmed-meshheading:11912178-Phenotype, pubmed-meshheading:11912178-Time Factors, pubmed-meshheading:11912178-Trinucleotide Repeats
pubmed:year
2002
pubmed:articleTitle
Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice.
pubmed:affiliation
Molecular Neurogenetics Unit and Molecular Neuropathology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't