title: A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation.
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 systematic manner, 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208.
authors.forename: Prajwal
authors.initials: P
authors.lastname: Ciryam
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors.forename: Rishika
authors.initials: R
authors.lastname: Kundra
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors.forename: Rosie
authors.initials: R
authors.lastname: Freer
authors.affiliation: Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D009419:Nerve Tissue Proteins; D020543:Proteome
keywords: amyloid formation; neurodegenerative diseases; protein aggregation; protein misfolding; protein supersaturation