A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation

Prajwal Ciryam, Rishika Kundra, Rosie Freer, Richard I. Morimoto, Christopher M. Dobson, Michele Vendruscolo*

*Corresponding author for this work

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer's disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction. To address this problem in a systematicmanner, we performed a meta-analysis of about 1,600 microarrays from human central nervous system tissues to identify transcriptional changes upon aging and as a result of Alzheimer's disease. Our strategy to discover a transcriptional signature of Alzheimer's disease revealed a set of down-regulated genes that encode proteins metastable to aggregation. Using this approach, we identified a small number of biochemical pathways, notably oxidative phosphorylation, enriched in proteins vulnerable to aggregation in control brains and encoded by genes down-regulated in Alzheimer's disease. These results suggest that the down-regulation of a metastable subproteome may help mitigate aberrant protein aggregation when protein homeostasis becomes compromised in Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)4753-4758
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number17
DOIs
StatePublished - Apr 26 2016

Keywords

  • Amyloid formation
  • Neurodegenerative diseases
  • Protein aggregation
  • Protein misfolding
  • Protein supersaturation

ASJC Scopus subject areas

  • General

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