Linked Life Data

11431533

Source:http://linkedlifedata.com/resource/pubmed/id/11431533

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5528
pubmed:dateCreated
2001-7-13
pubmed:abstractText
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive accumulation in selected neurons of protein inclusions containing alpha-synuclein and ubiquitin. Rare inherited forms of PD are caused by autosomal dominant mutations in alpha-synuclein or by autosomal recessive mutations in parkin, an E3 ubiquitin ligase. We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive PD. We have now identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UbcH7 as its associated E2 ubiquitin conjugating enzyme, and a new 22-kilodalton glycosylated form of alpha-synuclein (alphaSp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive PD failed to bind alphaSp22. In an in vitro ubiquitination assay, alphaSp22 was modified by normal but not mutant parkin into polyubiquitinated, high molecular weight species. Accordingly, alphaSp22 accumulated in a non-ubiquitinated form in parkin-deficient PD brains. We conclude that alphaSp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathological alphaSp22 accumulation. These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional PD.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0036-8075
pubmed:author
pubmed:issnType
Print
pubmed:day
13
pubmed:volume
293
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
263-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11431533-Brain, pubmed-meshheading:11431533-Brain Stem, pubmed-meshheading:11431533-Cell Line, pubmed-meshheading:11431533-Detergents, pubmed-meshheading:11431533-Freezing, pubmed-meshheading:11431533-Glycosylation, pubmed-meshheading:11431533-Humans, pubmed-meshheading:11431533-Lewy Bodies, pubmed-meshheading:11431533-Ligases, pubmed-meshheading:11431533-Mutation, Missense, pubmed-meshheading:11431533-Nerve Tissue Proteins, pubmed-meshheading:11431533-Parkinson Disease, pubmed-meshheading:11431533-Parkinsonian Disorders, pubmed-meshheading:11431533-Substrate Specificity, pubmed-meshheading:11431533-Synucleins, pubmed-meshheading:11431533-Ubiquitin-Conjugating Enzymes, pubmed-meshheading:11431533-Ubiquitin-Protein Ligases, pubmed-meshheading:11431533-Ubiquitins, pubmed-meshheading:11431533-alpha-Synuclein
pubmed:year
2001
pubmed:articleTitle
Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson's disease.
pubmed:affiliation
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't