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          Document History for Document ID 548977

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Document Version Version Comment Date Status
548977.0 [No comment] 23.03.2011 15:14 Released

ID: 548977.0, MPI für molekulare Genetik / Department of Vertebrate Genomics
Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation.
Authors:Viswanathan, J.; Haapasalo, A.; Böttcher, C.; Miettinen, R.; Kurkinen, K. M.; Lu, A.; Thomas, A.; Maynard, C. J.; Romano, D.; Hyman, B. T.; Berezovska, O.; Bertram, L.; Soininen, H.; Dantuma, N. P.; Tanzi, R. E.; Hiltunen, M.
Language:English
Date of Publication (YYYY-MM-DD):2011-02-10
Title of Journal:Traffic
Journal Abbrev.:Traffic
Volume:12
Issue / Number:3
Start Page:330
End Page:348
Copyright:© 2011 John Wiley & Sons A/S
Review Status:not specified
Audience:Experts Only
Abstract / Description:The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). PS-dependent gamma-secretase generates beta-amyloid (Abeta) peptides, which excessively accumulate in AD brain. Here, we have characterized the effects of naturally occurring ubiquilin-1 transcript variants (TVs) on the levels and subcellular localization of PS1 and other gamma-secretase complex components and subsequent gamma-secretase function in human embryonic kidney 293, human neuroblastoma SH-SY5Y and mouse primary cortical cells. Full-length ubiquilin-1 TV1 and TV3 that lacks the proteasome-interaction domain increased full-length PS1 levels as well as induced accumulation of high-molecular-weight PS1 and aggresome formation. Accumulated PS1 colocalized with TV1 or TV3 in the aggresomes. Electron microscopy indicated that aggresomes containing TV1 or TV3 were targeted to autophagosomes. TV1- and TV3-expressing cells did not accumulate other unrelated proteasome substrates, suggesting that the increase in PS1 levels was not because of a general impairment of the ubiquitin-proteasome system. Furthermore, PS1 accumulation and aggresome formation coincided with alterations in Abeta levels, particularly in cells overexpressing TV3. These effects were not related to altered gamma-secretase activity or PS1 binding to TV3. Collectively, our results indicate that specific ubiquilin-1 TVs can cause PS1 accumulation and aggresome formation, which may impact AD pathogenesis or susceptibility.
Free Keywords:β-amyloid precursor protein;
high-molecular-weight forms;
PEN-2;
proteasomal degradation;
transcript variant
Comment of the Author/Creator:Correspondence: Mikko Hiltunen,mikko.hiltunen@uef.fi
External Publication Status:published
Document Type:Article
Communicated by:Hans Lehrach
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute of Clinical Medicine—Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland;
2.Department of Neurology, Kuopio University Hospital, Kuopio, Finland;
3.Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden;
4.CNServices Ltd, Kuopio, Finland;
5.Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA;
6.MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Massachusetts Alzheimer Disease Research Center, Harvard Medical School, Charlestown, MA, USA.
Identifiers:ISSN:1398-9219 [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=... [ID No:2]
DOI:10.1111/j.1600-0854.2010.01149.x [ID No:3]
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