Crosstalk between the ubiquitin–proteasome system and autophagy in a human cellular model of Alzheimer's disease

Abstract

Alzheimer's disease is the most common progressive neurodegenerative disorder characterized by the abnormal deposition of amyloid plaques, likely as a consequence of an incorrect processing of the amyloid-β precursor protein (AβPP). Dysfunctions in both the ubiquitin-proteasome system and autophagy have also been observed. Recently, an extensive cross-talk between these two degradation pathways has emerged, but the exact implicated processes are yet to be clarified. In this work, we gained insight into such interplay by analyzing human SH-SY5Y neuroblastoma cells stably transfected either with wild-type AβPP gene or 717 valine-to-glycine AβPP-mutated gene. The over-expression of the AβPP mutant isoform correlates with an increase in oxidative stress and a remodeled pattern of protein degradation, with both marked inhibition of proteasome activities and impairment in the autophagic flux. To compensate for this altered scenario, cells try to promote the autophagy activation in a HDAC6-dependent manner. The treatment with amyloid-β(42) oligomers further compromises proteasome activity and also contributes to the inhibition of cathepsin-mediated proteolysis, finally favoring the neuronal degeneration and suggesting the existence of an Aβ(42) threshold level beyond which proteasome-dependent proteolysis becomes definitely dysfunctional.

Changes of intracellular Ca<sup>2+</sup> in quercetin-induced autophagy progression

“…Meanwhile, competitive crosstalk between the ubiquitin-proteasome system and autophagy has also been recently reported. For example, when quercetin inhibited proteasomal activity, polyubiquitinated protein aggregates were accumulated and autophagy was increase via marked reduction in the phosphorylation of the mTOR substrates [21,22]. These results suggested that quercetin can be an autophagy inducer.…”

Relationship between amyloid-beta and the ubiquitin–proteasome system in Alzheimer’s disease

“…8 According to the study by Cecarini et al, the over-expression of the amyloid precursor protein (APP) AD-linked mutant isoform in human SH-SY5Y neuroblastoma cells correlates with a remodeled pattern of protein degradation with marked inhibition of proteasome activities and impairment in the autophagic flux. 9 Although some proteins can be degraded by 20S proteasome in a way independent of ATP and ubiquitin, 10 the degradation of Abeta requires ATP and the ubiquitination process. So, elucidating the relationship between Abeta and UPS, two most crucial factors in AD, is of great importance to the understanding of the pathogenesis of this common and severe neurodegenerative disorder and to the searching of novel pharmacological targets for AD treatment.…”

Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels

“…Amyloid deposits and neurofibrillary tangles, comprising hyper phosphorylated tau protein, are the most important pathologic hallmarks of AD. Aβ deposition and clearance are finely regulated by the ubiquitin–proteasome system (UPS) and autophagy, which are tightly interrelated 1–4 . Impairment of proteolysis, which is characteristic of AD neurons, favors the accumulation of detrimental Aβ oligomeric structures that further contribute to proteasome and autophagy alterations.…”