Unknown

Dataset Information

0

Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1 accumulation and aggresome formation.


ABSTRACT: The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). PS-dependent ?-secretase generates ?-amyloid (A?) 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 ?-secretase complex components and subsequent ?-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? levels, particularly in cells overexpressing TV3. These effects were not related to altered ?-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.

SUBMITTER: Viswanathan J 

PROVIDER: S-EPMC3050036 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

altmetric image

Publications


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 neurobl  ...[more]

Similar Datasets

| S-EPMC2169435 | biostudies-literature
| S-EPMC1276952 | biostudies-other
| S-EPMC7471500 | biostudies-literature
| S-EPMC1794689 | biostudies-literature
| S-EPMC2850581 | biostudies-literature
| S-EPMC3973081 | biostudies-literature
| S-EPMC3018662 | biostudies-literature
| S-EPMC6521963 | biostudies-literature
| S-EPMC2797896 | biostudies-literature
| S-EPMC5603661 | biostudies-literature