UBB+1 reduces amyloid-β cytotoxicity by activation of autophagy in yeast.

Xin Chen,Dina Petranovic,Ana Joyce Muñoz-Arellano

doi:10.18632/aging.203681

Xin Chen, Dina Petranovic + Show 1 more

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https://doi.org/10.18632/aging.203681

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Abstract

UBB+1 is a mutated version of ubiquitin B peptide caused by a transcriptional frameshift due to the RNA polymerase II “slippage”. The accumulation of UBB+1 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+1 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+1 expression activated the autophagy pathway, increased vacuolar activity, and promoted transport of autophagic marker ATG8p into vacuole. Furthermore, we introduced low UBB+1 expression to our humanized yeast AD models, that constitutively express Aβ42 and Aβ40 peptide, respectively. The co-expression of UBB+1 with Aβ42 or Aβ40 peptide led to reduced intracellular Aβ levels, ameliorated viability, and increased chronological life span. In an autophagy deficient background strain (atg1Δ), intracellular Aβ levels were not affected by UBB+1 expression. Our findings offer insights for reducing intracellular Aβ toxicity via autophagy-dependent cellular pathways under low level of UBB+1 expression.

Highlights

Proteins are frequently misfolded during the lifetime of a cell, as a consequence of stochastic fluctuations of the structures, genomic mutations, oxidation or other different stress conditions [1]
To gain more insight into biological processes affected by L-Ubiquitin B gene (UBB)+1 expression, we performed the gene set enrichment analysis (GSA) on the significantly differentially expressed genes
Ubiquitin B+1 (UBB+1) has been found to accumulate in the brain of Alzheimer’s disease (AD) patients [52] and it is believed that it might contribute to the development of neuropathology of AD [53], a humanized yeast model by using heterologous expression of UBB+1 in yeast, could provide insights into its role(s) in vivo

Summary

Introduction

Proteins are frequently misfolded during the lifetime of a cell, as a consequence of stochastic fluctuations of the structures, genomic mutations, oxidation or other different stress conditions [1]. Accumulation of misfolded proteins within cellular compartments or tissues is emerging as a major contributor or even a causative agent in human diseases which are called “conformational diseases” [3]. These include a diverse array of pathologies such as lysosomal storage diseases [4], cystic fibrosis [5] and many neurodegenerative disorders [6, 7]. In addition to diseasecausing proteins (e.g., amyloid β, alpha-synuclein, or Huntingtin), there are often disruptions in the Ubiquitin B gene (UBB) and mRNA transcripts, as well as polyubiquitin depositions within aggregates made of disease-specific proteins. Unlike the UBB, UBB+1 fails to ligate protein substrates or join polyubiquitin chains due to the absence of the C-terminal glycine residue, but like any other damaged protein recognized by the UPS system, it is readily ubiquitylated and degraded [13, 14]

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