期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 17, 页码 4753-4758出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1516604113
关键词
neurodegenerative diseases; amyloid formation; protein misfolding; protein aggregation; protein supersaturation
资金
- US-UK Fulbright Commission
- National Institutes of Health (Northwestern University Medical Scientist Training Program Grant) [T32 GM8152-28]
- National Institutes of Health (National Institute of General Medical Sciences)
- National Institutes of Health (National Institute on Aging)
- National Institutes of Health (National Institute of Neurological Disorders and Stroke)
- Ellison Medical Foundation
- Daniel F. and Ada L. Rice Foundation
- Wellcome Trust
- Glenn Foundation
- St. John's College, University of Cambridge
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 micro-arrays 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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