Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation
| Autor: | Christa J. Maynard, Bradley T. Hyman, Nico P. Dantuma, Hilkka Soininen, Anne V. Thomas, Claudia Böttcher, Jayashree Viswanathan, Kaisa M.A. Kurkinen, Lars Bertram, Alice Lu, Rudolph E. Tanzi, Mikko Hiltunen, Annakaisa Haapasalo, Oksana Berezovska, Donna M. Romano, Riitta Miettinen |
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| Rok vydání: | 2011 |
| Předmět: |
Proteasome Endopeptidase Complex
Autophagy-Related Proteins Gene Expression Cell Cycle Proteins Mice Transgenic Models Biological Biochemistry Article Presenilin Mice Alzheimer Disease Structural Biology PEN-2 Phagosomes mental disorders Presenilin-1 Genetics medicine Animals Humans Molecular Biology Cells Cultured Adaptor Proteins Signal Transducing biology Protein Stability HEK 293 cells Signal transducing adaptor protein Cell Biology medicine.disease Subcellular localization Molecular biology nervous system diseases Cell biology HEK293 Cells Aggresome Proteasome biology.protein Amyloid Precursor Protein Secretases Alzheimer's disease Carrier Proteins |
| Zdroj: | Traffic. 12:330-348 |
| ISSN: | 1398-9219 |
| Popis: | The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). PS-dependent γ-secretase generates β-amyloid (Aβ) 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 γ-secretase complex components and subsequent γ-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 Aβ levels, particularly in cells overexpressing TV3. These effects were not related to altered γ-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. |
| Databáze: | OpenAIRE |
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