Linked Life Data

12473081

Source:http://linkedlifedata.com/resource/pubmed/id/12473081

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2002-12-10
pubmed:abstractText
Neurodegenerative disorders such as Parkinson's disease (PD) and 'dementia with Lewy bodies' (DLB) are characterized pathologically by selective neuronal death and the appearance of intracytoplasmic protein aggregates (Lewy bodies). The process by which these inclusions are formed and their role in the neurodegenerative process remain elusive. In this study, we demonstrate a close relationship between Lewy bodies and aggresomes, which are cytoplasmic inclusions formed at the centrosome as a cytoprotective response to sequester and degrade excess levels of potentially toxic abnormal proteins within cells. We show that the centrosome/aggresome-related proteins gamma-tubulin and pericentrin display an aggresome-like distribution in Lewy bodies in PD and DLB. Lewy bodies also sequester the ubiquitin-activating enzyme (E1), the proteasome activators PA700 and PA28, and HSP70, all of which are recruited to aggresomes for enhanced proteolysis. Using novel antibodies that are specific and highly sensitive to ubiquitin-protein conjugates, we revealed the presence of numerous discrete ubiquitinated protein aggregates in neuronal soma and processes in PD and DLB. These aggregates appear to be being transported from peripheral sites to the centrosome where they are sequestered to form Lewy bodies in neurons. Finally, we have shown that inhibition of proteasomal function or generation of misfolded proteins cause the formation of aggresome/Lewy body-like inclusions and cytotoxicity in dopaminergic neurons in culture. These observations suggest that Lewy body formation may be an aggresome-related event in response to increasing levels of abnormal proteins in neurons. This phenomenon is consistent with growing evidence that altered protein handling underlies the etiopathogenesis of PD and related disorders.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0953-816X
pubmed:author
pubmed:issnType
Print
pubmed:volume
16
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2136-48
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:12473081-Acetylcysteine, pubmed-meshheading:12473081-Antigens, pubmed-meshheading:12473081-Brain, pubmed-meshheading:12473081-Canavanine, pubmed-meshheading:12473081-Centrosome, pubmed-meshheading:12473081-Dose-Response Relationship, Drug, pubmed-meshheading:12473081-Golgi Apparatus, pubmed-meshheading:12473081-HSP70 Heat-Shock Proteins, pubmed-meshheading:12473081-Humans, pubmed-meshheading:12473081-Immunohistochemistry, pubmed-meshheading:12473081-Lewy Bodies, pubmed-meshheading:12473081-Lewy Body Disease, pubmed-meshheading:12473081-Nerve Tissue Proteins, pubmed-meshheading:12473081-Neurons, pubmed-meshheading:12473081-Parkinson Disease, pubmed-meshheading:12473081-Peptide Hydrolases, pubmed-meshheading:12473081-Protein Folding, pubmed-meshheading:12473081-Synucleins, pubmed-meshheading:12473081-Tubulin, pubmed-meshheading:12473081-Ubiquitins
pubmed:year
2002
pubmed:articleTitle
Aggresome-related biogenesis of Lewy bodies.
pubmed:affiliation
Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One Gustave L Levy Place, New York, NY 10029, USA. Kevin.mcnaught@mssm.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't