Hilfe Wegweiser Datenschutzhinweis Impressum Kontakt





Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation.


Bertram,  L.
Neuropsychiatric Genetics (Lars Bertram), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society;

Externe Ressourcen
Es sind keine Externen Ressourcen verfügbar
Volltexte (frei zugänglich)
Es sind keine frei zugänglichen Volltexte verfügbar
Ergänzendes Material (frei zugänglich)
Es sind keine frei zugänglichen Ergänzenden Materialien verfügbar

Viswanathan, J., Haapasalo, A., Böttcher, C., Miettinen, R., Kurkinen, K. M., Lu, A., et al. (2011). Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation. Traffic, 12(3), 330-348. doi:10.1111/j.1600-0854.2010.01149.x.

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.