title: 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 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.
authors.affiliation: Institute of Clinical Medicine-Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Viswanathan
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.forename: Claudia
authors.initials: C
authors.lastname: Böttcher
authors.forename: Riitta
authors.initials: R
authors.lastname: Miettinen
authors.forename: Kaisa M A
authors.initials: KM
authors.lastname: Kurkinen
authors.forename: Alice
authors.initials: A
authors.lastname: Lu
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Christa J
authors.initials: CJ
authors.lastname: Maynard
authors.forename: Donna
authors.initials: D
authors.lastname: Romano
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D053764:Presenilin-1; C107792:UBQLN1 protein, human; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex