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 fulllength 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 ubiquitinproteasome 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.

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

“…Some neuropathic mutations, however, may interfere more broadly with the normal clearance of diverse misfolded and aggregated proteins. Proteins harboring those mutations include ubiquilin‐1, leading to presenilin aggregation (mutated in some familial AD) (Viswanathan et al ., 2011); ubiquilin‐2 which also targets ubiquitinylated proteins to proteasomes (mutated in ALS) (Zhang et al ., 2014); and parkin, an E3 ubiquitin ligase required for mono‐ubiquitin addition to specific protein targets (mutated in PD) (Roy et al ., 2015). Other predisposing factors can markedly elevate the risk of specific neurological diseases, for example, brain trauma, epilepsy, hypertension, obesity, type 2 diabetes, and exposure to toxic chemicals (in AD, PD) (Vosler et al ., 2008; Zigman, 2013).…”

The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

“…Thus, centrosomal proteasomes may act as substrate sensors, using their non-degradative enzymatic activities to influence the ubiquitin profile of the cell, provoking an alternative degradation strategy. Since many neurodegenerative disorders involve aggregation of cytotoxic proteins, it is not surprising that aggresomes and aggresome-like inclusions appear in several disease states such as Parkinson, 27 Alzheimer, 33 Huntington's, 34 and multiple myeloma. 35 Future studies elucidating the explicit role of the centrosome in coordinating cellular response to unfolded protein stress should provide important insights into the pathophysiology of diseases vulnerable to defects in protein degradation.…”

Inefficient Translocation of Preproinsulin Contributes to Pancreatic β Cell Failure and Late-onset Diabetes

“…Because juxtanuclear accumulation of misfolded protein has been linked to cell death in neurodegenerative diseases (37,38), we asked whether accumulation of preproinsulin R6C affects cell viability and proliferation. No appreciable change of BrdU incorporation was observed between cells expressing Myctagged preproinsulin WT and R6C (Fig.…”