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Alzheimer's Disease‐Associated Ubiquilin‐1 Regulates Presenilin‐1 Accumulation and Aggresome Formation
Author(s) -
Viswanathan Jayashree,
Haapasalo Annakaisa,
Böttcher Claudia,
Miettinen Riitta,
Kurkinen Kaisa M. A.,
Lu Alice,
Thomas Anne,
Maynard Christa J.,
Romano Donna,
Hyman Bradley T.,
Berezovska Oksana,
Bertram Lars,
Soininen Hilkka,
Dantuma Nico P.,
Tanzi Rudolph E.,
Hiltunen Mikko
Publication year - 2011
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2010.01149.x
Subject(s) - aggresome , presenilin , proteasome , microbiology and biotechnology , biology , ubiquitin , chemistry , disease , medicine , genetics , alzheimer's disease , gene
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.