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Journal Article

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;

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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.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0010-77C2-4
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.