Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain
Abstract Background All cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be...
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doaj-2d2aa71f62ab406e8c0f10373ce85c5c2020-11-25T03:15:10ZengBMCAlzheimer’s Research & Therapy1758-91932020-06-0112112010.1186/s13195-020-00641-2Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brainDevin Kepchia0Ling Huang1Richard Dargusch2Robert A. Rissman3Maxim N. Shokhirev4Wolfgang Fischer5David Schubert6Cellular Neurobiology Laboratory, The Salk Institute for Biological StudiesThe Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological StudiesCellular Neurobiology Laboratory, The Salk Institute for Biological StudiesDepartment of Neurosciences and Shiley-Marcos Alzheimer’s Disease Research Center Neuropathology Core, University of CaliforniaThe Razavi Newman Integrative Genomics and Bioinformatics Core, The Salk Institute for Biological StudiesCellular Neurobiology Laboratory, The Salk Institute for Biological StudiesCellular Neurobiology Laboratory, The Salk Institute for Biological StudiesAbstract Background All cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be directly associated with disease and lifespan. Methods A proteomics approach was used to identify a large subset of insoluble proteins in the mild cognitively impaired (MCI) and Alzheimer’s disease (AD) human brain. Cortical samples from control, MCI, and AD patients were separated into detergent-soluble and detergent-insoluble fractions, and high-resolution LC/MS/MS technology was used to determine which proteins became more insoluble in the disease state. Bioinformatics analyses were used to determine if the alteration of protein aggregation between AD and control patients was associated with any specific biological process. Western blots were used to validate the proteomics data and to assess the levels of secondary protein modifications in MCI and AD. Results There was a stage-dependent increase in detergent-insoluble proteins, with more extreme changes occurring in the AD cohort. Glycolysis was the most significantly overrepresented gene ontology biological process associated with the alteration of protein aggregation between AD and control patients. It was further shown that many low molecular weight proteins that were enriched in the AD brain were also highly aggregated, migrating on SDS-PAGE far above their predicted molecular masses. Glucose-6-phosphate isomerase, ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1/PARK5), and the DNA damage repair enzyme KU70 were among the top insoluble proteins identified by proteomics and validated by Western blot to be increased in the insoluble fractions of both MCI and AD brain samples. Conclusions Diverse proteins became more detergent-insoluble in the brains of both MCI and AD patients compared to age-matched controls, suggesting that multiple proteins aggregate in these diseases, likely posing a direct toxic insult to neurons. Furthermore, detergent-insoluble proteins included those with important biological activities for critical cellular processes such as energetics, proteolysis, and DNA damage repair. Thus, reduced protein solubility likely promotes aggregation and limits functionality, reducing the efficiency of multiple aspects of cell physiology. Pharmaceutical interventions that increase autophagy may provide a useful therapeutic treatment to combat protein aggregation.http://link.springer.com/article/10.1186/s13195-020-00641-2DementiaInsoluble proteinSecondary modificationsProteomicsBioinformatics |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Devin Kepchia Ling Huang Richard Dargusch Robert A. Rissman Maxim N. Shokhirev Wolfgang Fischer David Schubert |
spellingShingle |
Devin Kepchia Ling Huang Richard Dargusch Robert A. Rissman Maxim N. Shokhirev Wolfgang Fischer David Schubert Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain Alzheimer’s Research & Therapy Dementia Insoluble protein Secondary modifications Proteomics Bioinformatics |
author_facet |
Devin Kepchia Ling Huang Richard Dargusch Robert A. Rissman Maxim N. Shokhirev Wolfgang Fischer David Schubert |
author_sort |
Devin Kepchia |
title |
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain |
title_short |
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain |
title_full |
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain |
title_fullStr |
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain |
title_full_unstemmed |
Diverse proteins aggregate in mild cognitive impairment and Alzheimer’s disease brain |
title_sort |
diverse proteins aggregate in mild cognitive impairment and alzheimer’s disease brain |
publisher |
BMC |
series |
Alzheimer’s Research & Therapy |
issn |
1758-9193 |
publishDate |
2020-06-01 |
description |
Abstract Background All cells accumulate insoluble protein aggregates throughout their lifespan. While many studies have characterized the canonical disease-associated protein aggregates, such as those associated with amyloid plaques, additional, undefined proteins aggregate in the brain and may be directly associated with disease and lifespan. Methods A proteomics approach was used to identify a large subset of insoluble proteins in the mild cognitively impaired (MCI) and Alzheimer’s disease (AD) human brain. Cortical samples from control, MCI, and AD patients were separated into detergent-soluble and detergent-insoluble fractions, and high-resolution LC/MS/MS technology was used to determine which proteins became more insoluble in the disease state. Bioinformatics analyses were used to determine if the alteration of protein aggregation between AD and control patients was associated with any specific biological process. Western blots were used to validate the proteomics data and to assess the levels of secondary protein modifications in MCI and AD. Results There was a stage-dependent increase in detergent-insoluble proteins, with more extreme changes occurring in the AD cohort. Glycolysis was the most significantly overrepresented gene ontology biological process associated with the alteration of protein aggregation between AD and control patients. It was further shown that many low molecular weight proteins that were enriched in the AD brain were also highly aggregated, migrating on SDS-PAGE far above their predicted molecular masses. Glucose-6-phosphate isomerase, ubiquitin carboxyl-terminal hydrolase isoenzyme L1 (UCHL1/PARK5), and the DNA damage repair enzyme KU70 were among the top insoluble proteins identified by proteomics and validated by Western blot to be increased in the insoluble fractions of both MCI and AD brain samples. Conclusions Diverse proteins became more detergent-insoluble in the brains of both MCI and AD patients compared to age-matched controls, suggesting that multiple proteins aggregate in these diseases, likely posing a direct toxic insult to neurons. Furthermore, detergent-insoluble proteins included those with important biological activities for critical cellular processes such as energetics, proteolysis, and DNA damage repair. Thus, reduced protein solubility likely promotes aggregation and limits functionality, reducing the efficiency of multiple aspects of cell physiology. Pharmaceutical interventions that increase autophagy may provide a useful therapeutic treatment to combat protein aggregation. |
topic |
Dementia Insoluble protein Secondary modifications Proteomics Bioinformatics |
url |
http://link.springer.com/article/10.1186/s13195-020-00641-2 |
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