Linked Life Data

21854390

Source:http://linkedlifedata.com/resource/pubmed/id/21854390

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2011-10-6
pubmed:abstractText
Huntington's disease is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. This expansion produces a mutant form of the huntingtin protein, which contains an elongated polyglutamine stretch at its amino-terminus. Mutant huntingtin may adopt an aberrant, aggregation-prone conformation predicted to start the pathogenic process leading to neuronal dysfunction and cell death. Thus, strategies reducing mutant huntingtin may lead to disease-modifying therapies. We investigated the mechanisms and molecular targets regulating huntingtin degradation in a neuronal cell model. We first found that mutant and wild-type huntingtin displayed strikingly diverse turn-over kinetics and sensitivity to proteasome inhibition. Then, we show that autophagy induction led to accelerate degradation of mutant huntingtin aggregates. In our neuronal cell model, allosteric inhibition of mTORC1 by everolimus, a rapamycin analogue, did not induce autophagy or affect aggregate degradation. In contrast, this occurred in the presence of catalytic inhibitors of both mTOR complexes mTORC1 and mTORC2. Our data demonstrate the existence of an mTOR-dependent but everolimus-independent mechanism regulating autophagy and huntingtin-aggregate degradation in cells of neuronal origin.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1471-4159
pubmed:author
pubmed:copyrightInfo
© 2011 Novartis Pharma AG. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
pubmed:issnType
Electronic
pubmed:volume
119
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
398-407
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Induction of autophagy with catalytic mTOR inhibitors reduces huntingtin aggregates in a neuronal cell model.
pubmed:affiliation
Novartis Institutes for BioMedical Research, Neuroscience Discovery, Basel, Switzerland.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't