P2‐281: Alzheimer's disease‐associated ubiquilin‐1 regulates presenilin‐1 accumulation and aggresome formation
Year: 2010
Type: article
Abstract: Ubiquilin-1 is a ubiquitin-like protein genetically and functionally associated to Alzheimer's disease (AD). It interacts with the proteasome and binds poly-ubiquitinated proteins. Ubiquilin-1 regulates proteasomal degradation of proteins including the AD-associated presenilin-1 (PS1) and causes PS1 accumulation. Ubiquilin-1 is suggested to play a role also in other neurodegenerative diseases involving abnormal protein accumulation. Here we characterized the effects of different naturally occurring ubiquilin-1 transcript variants (TV), full-length TV1 and TV3 lacking the proteasome-interaction domain, on PS1 accumulation and ubiquitin-proteasome system (UPS). TV1 or TV3 and PS1 cDNAs were transiently transfected to human embryonic kidney (HEK293) cells overexpressing alkaline phophatase-conjugated amyloid precursor protein (AP-APP) and primary embryonic cortical cells from transgenic mice overexpressing APP and PS1 with the delta-exon-9 mutation. The effects of TV1 and TV3 on PS1 accumulation and beta-amyloid production were assessed by Western blotting, fluorescence and electron microscopy (EM) and enzyme-linked immunosorbent assay. The impact of the TVs on UPS was studied in HEK293T cells overexpressing UbG76V-yellow fluorescent protein proteasomal reporter substrate. Co-expression of especially TV3 with PS1 strongly induced the accumulation of high-molecular-weight PS1 and stabilized full-length PS1 levels. However, these effects were not caused by a general impairment of the UPS in TV1- or TV3-overexpressing cells. The accumulated PS1 co-localized with TV1 and TV3 in juxtanuclear aggresomes in both HEK293-AP-APP and cortical cells. Moreover, aggresome formation was significantly augmented in cells co-expressing PS1 and TV1 or TV3 as compared to control cells. EM confirmed the presence of TV1 and TV3 in the aggresomes and in the aggregates inside autophagosomes. PS1 accumulation and aggresome formation coincided with decreased production of beta-amyloid, particularly in TV3-expressing cells. Our results suggest that specific ubiquilin-1 TVs regulate PS1 accumulation and targeting into the aggresome-autophagosome pathway. PS1 sequestered in the aggresomes is not available for gamma-secretase complex assembly, and subsequently beta-amyloid production is decreased. Our data agree with the suggested function for ubiquilin-1 as a shuttle protein directing proteins to proteasomal degradation or to the aggresome-autophagosome pathway. Thus, ubiquilin-1 alternative splicing may be an important regulator of ubiquilin-1 function also in the context of AD pathogenesis.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1966808609