Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein

Emily S. Stieren, Amina El Ayadi, Yao Xiao, Efraín Siller, Megan L. Landsverk, Andres Oberhauser, José M. Barral, Darren Boehning

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Alzheimer disease (AD) is associated with extracellular deposition of proteolytic fragments of amyloid precursor protein (APP). Although mutations in APP and proteases that mediate its processing are known to result in familial, early onset forms of AD, the mechanisms underlying the more common sporadic, yet genetically complex forms of the disease are still unclear. Four single-nucleotide polymorphisms within the ubiquilin-1 gene have been shown to be genetically associated with AD, implicating its gene product in the pathogenesis of late onset AD. However, genetic linkage between ubiquilin-1 and AD has not been confirmed in studies examining different populations. Here we show that regardless of genotype, ubiquilin-1 protein levels are significantly decreased in late onset AD patient brains, suggesting that diminished ubiquilin function may be a common denominator in AD progression. Our interrogation of putative ubiquilin-1 activities based on sequence similarities to proteins involved in cellular quality control showed that ubiquilin-1 can be biochemically defined as a bona fide molecular chaperone and that this activity is capable of preventing the aggregation of amyloid precursor protein both in vitro and in live neurons. Furthermore, we show that reduced activity of ubiquilin-1 results in augmented production of pathogenic amyloid precursor protein fragments as well as increased neuronal death. Our results support the notion that ubiquilin-1 chaperone activity is necessary to regulate the production of APP and its fragments and that diminished ubiquilin-1 levels may contribute to AD pathogenesis.

Original languageEnglish (US)
Pages (from-to)35689-35698
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number41
DOIs
StatePublished - Oct 14 2011

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Molecular Chaperones
Amyloid beta-Protein Precursor
Alzheimer Disease
Genetic Linkage
Genes
Quality Control
Single Nucleotide Polymorphism
Disease Progression
Proteins
Peptide Hydrolases
Genotype
Polymorphism
Neurons
Mutation
Quality control
Brain
Agglomeration
Nucleotides
Population

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. / Stieren, Emily S.; El Ayadi, Amina; Xiao, Yao; Siller, Efraín; Landsverk, Megan L.; Oberhauser, Andres; Barral, José M.; Boehning, Darren.

In: Journal of Biological Chemistry, Vol. 286, No. 41, 14.10.2011, p. 35689-35698.

Research output: Contribution to journalArticle

Stieren, ES, El Ayadi, A, Xiao, Y, Siller, E, Landsverk, ML, Oberhauser, A, Barral, JM & Boehning, D 2011, 'Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein', Journal of Biological Chemistry, vol. 286, no. 41, pp. 35689-35698. https://doi.org/10.1074/jbc.M111.243147
Stieren, Emily S. ; El Ayadi, Amina ; Xiao, Yao ; Siller, Efraín ; Landsverk, Megan L. ; Oberhauser, Andres ; Barral, José M. ; Boehning, Darren. / Ubiquilin-1 is a molecular chaperone for the amyloid precursor protein. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 41. pp. 35689-35698.
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