Journal
TRAFFIC
Volume 12, Issue 3, Pages 330-348Publisher
WILEY
DOI: 10.1111/j.1600-0854.2010.01149.x
Keywords
beta-amyloid precursor protein; high-molecular-weight forms; PEN-2; proteasomal degradation; transcript variant
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Funding
- EC [MEST-CT-2005-019217]
- Health Research Council of the Academy of Finland
- EVO of Kuopio University Hospital [5772708]
- Nordic Centre of Excellence in Neurodegeneration
- Sigrid Juselius Foundation
- Swedish Research Council
- Wenner-Gren Foundation
- NIH [AG15379]
- Cure Alzheimer's Fund
- NIA
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The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). PS-dependent gamma-secretase generates beta-amyloid (A beta) 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 A beta 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.
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