UBB reduces amyloid-β cytotoxicity by activation of autophagy in yeast.

UBB is a mutated version of ubiquitin B peptide caused by a transcriptional frameshift due to the RNA polymerase II "slippage". The accumulation of UBB has been linked to ubiquitin-proteasome system (UPS) dysfunction and neurodegeneration. Alzheimer's disease (AD) is defined as a progressive neurodegeneration and aggregation of amyloid-β peptides (Aβ) is a prominent neuropathological feature of AD. In our previous study, we found that yeast cells expressing UBB at lower level display an increased resistance to cellular stresses under conditions of chronological aging. In order to examine the molecular mechanisms behind, here we performed genome-wide transcriptional analyses and molecular/cellular biology assays. We found that low UBB expression activated the autophagy pathway, increased vacuolar activity, and promoted transport of autophagic marker ATG8p into vacuole. Furthermore, we introduced low UBB expression to our humanized yeast AD models, that constitutively express Aβ42 and Aβ40 peptide, respectively. The co-expression of UBB with Aβ42 or Aβ40 peptide led to reduced intracellular Aβ levels, ameliorated viability, and increased chronological life span. In an autophagy deficient background strain (), intracellular Aβ levels were not affected by UBB expression. Our findings offer insights for reducing intracellular Aβ toxicity via autophagy-dependent cellular pathways under low level of UBB expression.