Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease
Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, Lah JJ, Levey AI et al.. Molecular neurodegeneration, 2018-10-04
Topic: Genetics and APOE
Background The complicated cellular and biochemical changes that occur in brain during Alzheimer's disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer's disease (AD), asymptomatic Alzheimer's disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies. Methods The amount of information that can be obtained from such systems-level proteomic analyses is critically dependent upon the number of proteins that can be quantified across a cohort. We report here a new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation. Results Our new TMT pipeline allowed us to more than double the depth of brain proteome coverage. This increased depth of coverage greatly expanded the brain protein network to reveal new protein modules that correlated with disease and were unrelated to those identified in our previous network. Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD. RNA binding proteins emerged as a class of proteins altered between AsymAD and AD, and were enriched in network modules that correlated with AD pathology. We developed a proteogenomic approach to investigate RNA splicing events that may be altered by RNA binding protein changes in AD. The increased proteome depth afforded by our TMT pipeline allowed us to identify and quantify a large number of alternatively spliced protein isoforms in brain, including AD risk factors such as BIN1, PICALM, PTK2B, and FERMT2. Many of the new AD protein network modules were enriched in alternatively spliced proteins and correlated with molecular markers of AD pathology and cognition. Conclusions Further analysis of the AD brain proteome will continue to yield new insights into the biological basis of AD.
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APA 7th
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Yin, L., Thambisetty, M., Troncoso, J. C., et al. (2018). Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Molecular neurodegeneration. https://doi.org/10.1186/s13024-018-0282-4
Vancouver
Johnson ECB, Dammer EB, Duong DM, Yin L, Thambisetty M, Troncoso JC, et al. Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Molecular neurodegeneration. 2018. doi:10.1186/s13024-018-0282-4. PMID: 30286791.
BibTeX
@article{johnson2018-30286791,
author = {Johnson, E. C. B. and Dammer, E. B. and Duong, D. M. and Yin, L. and Thambisetty, M. and Troncoso, J. C. and Lah, J. J. and Levey, A. I. and others},
title = {{Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease}},
journal = {Molecular neurodegeneration},
year = {2018},
doi = {10.1186/s13024-018-0282-4},
pmid = {30286791},
url = {https://doi.org/10.1186/s13024-018-0282-4}
}
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Key findings
- We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies.
- Results Our new TMT pipeline allowed us to more than double the depth of brain proteome coverage.
- Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD.
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Study details
- Evidence strengthModerate
How this study scored 45/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2018 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30286791) |
| Free to read | 2 / 2 | Free to read |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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