Human Brain Proteome

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Original Research ARTICLE

Expert Rev Proteomics 14 6 — Sun F, Cavalli V Neuroproteomics approaches to decipher neuronal regeneration and degeneration.

Medical Proteome Center

Mol Cell Proteomics 9 5 — Methods 61 3 — Neurosurgery 70 3 — Twiss JL, Fainzilber M Neuroproteomics: how many angels can be identified in an extract from the head of a pin? Mol Cell Proteomics 15 2 — Eur J Pharmacol 1—3 — Expert Rev Proteomics 5 2 — Exp Neurol 1 — Proteomics 3 10 — Brain Res Bull — Proteomics Clin Appl 9 9—10 — Expert Rev Proteomics 2 1 :1—3. I Brain proteins: separation by two-dimensional electrophoresis and identification by mass spectrometry and genetic variation. Electrophoresis 20 3 — Nat Genet 30 4 — Proteomics 6 18 — J Proteome Pt B — Mol Cell Proteomics 8 7 — Mol Neuropsychiatry 3 1 — J Proteome Res 16 8 — Nat Neurosci 18 12 — Fountoulakis M Application of proteomics technologies in the investigation of the brain.

The Brain Atlas

Mass Spectrom Rev 23 4 — Hum Mol Genet 23 22 — Doll S, Burlingame AL Mass spectrometry-based detection and assignment of protein posttranslational modifications. ACS Chem Biol 10 1 — Mol Psychiatry. Mol Cell Proteomics 17 7 — J Pathol 1 — Oxidative Med Cell Longev Oncotarget 7 25 — PLoS One 10 10 :e PLoS One 10 3 :e Mol Cell Proteomics 11 8 — In stage II, ptau lesions are found in multiple cortical regions. In stage III, extensive ptau pathology is found in medial temporal lobe structures like the hippocampus and amygdala. In stage IV, there is wide spread ptau involvement in all brain structures.

Three cases utilized in this study were labeled as having overlapping stages i. Cases with CTE that were used here did not meet diagnostic criteria for AD, PD, dementia with Lewy bodies, frontotemporal lobe degeneration, or motor neuron disease.

The Human Brain Proteome Project: Biological and Technological Challenges

A team of board certified neuropathologists T. Controls were selected based on a lack of history of contact sport play and lack of neurodegenerative diseases. Next of kin provided written consent for participation and brain donation. Immunohistochemistry of paraffin sections was performed as previously described The gray matter at the depth of the cortical sulci defined as the bottom third of 2 connecting gyri was selected and highlighted in ImagesScope Leica. NQO1-positive cells were counted by hand while AT8 area was quantified using Leica image analysis software.

The Aperio-positive pixel count algorithm version 9 was set to recognize and quantify the total area of-positive AT8 tau stain. All quantifications were standardized to area measured and presented as density per analyzed area. Statistical analysis was performed with SPSS version NQO1 and AT8 density were log transformed to normalize for regression analysis. For multiple linear regressions, age at death was included to control for age specific effects. Brain detergent insoluble fractions were generated as described previously from fresh frozen human lateral prefrontal cortex 13 , All attempts were made to utilize the same region for each brain.


The sample was sonicated followed by ultracentrifugation at , g. Four batches of TMT peptide mixtures plex were prepared and mixed such that batch-confounding by disease status or CTE stage was avoided, and each peptide batch was offline fractionated via ERLIC solid phase for liquid chromatography. At least 1 TMT-labeled channel in each batch was comprised of a multi-brain mixture representing all cases analyzed as a standard by which abundances across batches could be normalized. Normalized log2 reporter ion intensity ratio versus the global multi-brain mixture was used to compare protein expression across cases and batches.

The Student t -test 2-tailed was utilized to calculate p values and significance for the differentially enriched or depleted proteins.

eLife digest

Fold change comparison was calculated by subtracting the control log2 values from the CTE or AD log2 values. We were interested exploring this technique in cases of CTE, but the pathology is often irregular and patchy, particularly in earlier stages. We therefore used a similar approach for discovery of proteomic changes in CTE with using TMT labeling and off-line fractionation to improve the number of proteins identified and quantified. Volcano plots Fig. These plots provide perspective on numbers of significant proteins as well as the comparative significance of the expression change.

The Human Brain - Newton Howard - TEDxEroilor

To demonstrate stage specific changes, CTE cases were further divided into respective stages in the volcano plots shown in Supplementary Data Figure S1. Venn diagrams of significantly reduced and enriched insoluble proteins as compared to controls. S1 , including Uk. Enrichment of Uk and other members of the U1snRNP complex were previously identified in the insoluble proteome of AD in association with neurofibrillary tangle-like aggregates The limited overlap in the profile of differentially expressed proteins further distinguish CTE and AD as distinct pathologic entities.

Sections were from dorsolateral prefrontal cortex and images shown were from depths of the sulci. Inset figures provide a magnified view from each figure panel. Four stages have been described in CTE based on the overall density and distribution of tau pathology within the brain 15 , Previous work has suggested that increased pathologic burden of tau was associated with the development of dementia in CTE While the correlation between tau and symptom severity has not yet been firmly established, increasing pathology with higher stage is likely to reflect pathophysiological processes that may provide clues about disease pathogenesis and progression.

As previously noted, there is reason for concern that random sampling from earlier stage CTE cases might fail to capture disease related changes. Three instead of 4 groups were utilized due to the small number of cases. This finding is consistent with neuropathological observations that show more limited tau pathology in these lower CTE stages The top 25 most enriched proteins in the CTE IV subgroup included 4 proteins that demonstrated progressive enrichment with increasing stage across the 3 CTE subgroups.

There were also 3 other proteins kininogen 1 [KNG1] , mitochondrial ribosomal protein L32 MRPL32 , and voltage dependent anion channel 3 [VDAC3] that demonstrated significant enrichment in all groups, but did not show progressive enrichment with increasing pathological stage. These experiments demonstrate novel stage-specific changes identified by analyzing insoluble proteome changes across CTE severity.

The top 25 significantly enriched proteins are shown across increasing CTE stages. Seven of the top 25 stage IV proteins are also enriched in the first 2 groups.

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If the protein is not in the top 25, it is listed below the table with the position number on the list. Results from sequencing the insoluble proteome of CTE cases suggested previously unknown disease related changes. We sought to further evaluate the proteomic changes observed in CTE cases, including tissue localization by immunohistochemistry, to better understand the cellular basis for altered protein expression. NQO1 was also the most enriched of the 54 shared differentially expressed insoluble proteins in CTE across all stages Fig.

Additionally, previously published reports suggest that NQO1 may play a role in neurodegeneration 25— Since proteins in the detergent insoluble proteome are known to aggregate tau, amyloid, RNA processing factors , we performed immunohistochemical labeling of NQO1 to assess possible aberrant localization or accumulation in CTE and AD brains. Morphologically, the cells had the appearance of reactive astrocytes or possibly activated microglia.

NQO1-positive cellular processes frequently contacted microvasculature as seen in dual labeling experiments with CD31, further identifying these cells as astrocytes. Given the paucity of the NQO1-positive cells in control cases, dual labeling figures are also not shown. We also evaluated nuclear factor E2-related factor 2 NRF2 , an NQO1 transcription factor, in order to determine whether the increased NQO1 immunostaining was the result of increased cellular production of NRF2 in response to oxidative injury.

One whole sulcus was utilized for measuring NQO1 density in each case.

White arrows: foot processes from NQO1-positive cells. Sections utilized were from the depths of sulci from dorsolateral prefrontal cortex. The density of NQO1 stained cells significantly correlated with hyperphosphorylated tau immunostaining and NQO1 colocalized with tau immunostaining within these cells Fig.

"Human brain proteome in health and disease." by Renã A. Robinson, Melanie Föcking et al.

Almost all NQO1-positive cells also contained the abnormal accumulation of hyperphosphorylated tau Supplementary Data Fig. S4 Later stage CTE cases are typically from older individuals than earlier stage cases. These immunohistochemical studies validate findings from our proteomics studies and suggest that CTE is associated with aberrant expression of NQO1 in astrocytes and that NQO1 abnormalities correlate with the accumulation of tau pathology in increasing stages of CTE.

Yellow color in the merge image designates colocalization. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We are very grateful to the tissue donors and their families. We thank the Neurological Tissue Bank of Navarrabiomed for immunohistochemical analysis of the brains and for providing us the amygdala specimens. Adolphs, R. A mechanism for impaired fear recognition after amygdala damage. Nature , 68— Altelaar, A.

Next-generation proteomics: towards an integrative view of proteome dynamics. Andrews, G. Performance characteristics of a new hybrid quadrupole time-of-flight tandem mass spectrometer TripleTOF Aroniadou-Anderjaska, V. Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy.

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