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

doi:10.1073/pnas.1516604113

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

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

71 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 language	English (US)
Pages (from-to)	4753-4758
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	17
DOIs	https://doi.org/10.1073/pnas.1516604113
State	Published - Apr 26 2016

Funding

P.C. was supported by grants from the US-UK Fulbright Commission, St. John's College, University of Cambridge, and the National Institutes of Health (Northwestern University Medical Scientist Training Program Grant T32 GM8152-28). R.I.M. was supported by grants from the National Institutes of Health (National Institute of GeneralMedical Sciences, National Institute on Aging, National Institute of Neurological Disorders and Stroke), the Ellison Medical Foundation, the Glenn Foundation, and the Daniel F. and Ada L. Rice Foundation. C.M.D. and M.V. were supported by the Wellcome Trust.

Keywords

Amyloid formation
Neurodegenerative diseases
Protein aggregation
Protein misfolding
Protein supersaturation

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1073/pnas.1516604113

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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 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.",

keywords = "Amyloid formation, Neurodegenerative diseases, Protein aggregation, Protein misfolding, Protein supersaturation",

author = "Prajwal Ciryam and Rishika Kundra and Rosie Freer and Morimoto, {Richard I.} and Dobson, {Christopher M.} and Michele Vendruscolo",

note = "Funding Information: P.C. was supported by grants from the US-UK Fulbright Commission, St. John's College, University of Cambridge, and the National Institutes of Health (Northwestern University Medical Scientist Training Program Grant T32 GM8152-28). R.I.M. was supported by grants from the National Institutes of Health (National Institute of GeneralMedical Sciences, National Institute on Aging, National Institute of Neurological Disorders and Stroke), the Ellison Medical Foundation, the Glenn Foundation, and the Daniel F. and Ada L. Rice Foundation. C.M.D. and M.V. were supported by the Wellcome Trust.",

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A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation. / Ciryam, Prajwal; Kundra, Rishika; Freer, Rosie et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 17, 26.04.2016, p. 4753-4758.

Research output: Contribution to journal › Article › peer-review

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T1 - A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation

AU - Ciryam, Prajwal

AU - Kundra, Rishika

AU - Freer, Rosie

AU - Morimoto, Richard I.

AU - Dobson, Christopher M.

AU - Vendruscolo, Michele

N1 - Funding Information: P.C. was supported by grants from the US-UK Fulbright Commission, St. John's College, University of Cambridge, and the National Institutes of Health (Northwestern University Medical Scientist Training Program Grant T32 GM8152-28). R.I.M. was supported by grants from the National Institutes of Health (National Institute of GeneralMedical Sciences, National Institute on Aging, National Institute of Neurological Disorders and Stroke), the Ellison Medical Foundation, the Glenn Foundation, and the Daniel F. and Ada L. Rice Foundation. C.M.D. and M.V. were supported by the Wellcome Trust.

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N2 - 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.

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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