Neurology-related protein biomarkers are associated with cognitive ability and brain volume in older age

Harris, Sarah E.; Cox, Simon R.; Bell, Steven; Marioni, Riccardo E.; Prins, Bram P.; Pattie, Alison; Corley, Janie; Maniega, Susana Muñoz; Hernández, Maria Valdés; Morris, Zoë; John, Sally; Bronson, Paola G.; Tucker‐Drob, Elliot M.; Starr, John M.; Wardlaw, Joanna M.; Butterworth, Adam S.; Deary, Ian J.

doi:10.1038/s41467-019-14161-7

Cited by 49 publications

(54 citation statements)

References 63 publications

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“…Synuclein is thought to be a marker of Parkinson’s disease and it has been studied in AD [ 11 ]. Protein arrays showed that ectodysplasin A2 receptor (EDA2R), Poliovirus receptor (PVR) and discoidin domain receptor family, member 1 (DDR1) were potential biomarkers of AD [ 12 ]. An array of nucleic acid aptamers was used to identify 44 proteins that apparently showed modest enrichments in AD but that showed no significant protein interactions, and APOE was the strongest correlate with amyloid burden [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The plasma peptides of Alzheimer’s disease

Florentinus-Mefailoski

Bowden

Scheltens

et al. 2021

Clin Proteom

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Background A practical strategy to discover proteins specific to Alzheimer’s dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer’s were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice. Methods Endogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC–ESI–MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log10 precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system. Results Peptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls. Conclusion Proteins apparently expressed in the brain that were directly related to Alzheimer’s including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma vs the matched control. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA.

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Section: Introductionmentioning

confidence: 99%

The plasma peptides of Alzheimer’s disease

Florentinus-Mefailoski

Bowden

Scheltens

et al. 2021

Clin Proteom

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“…VWC2 (also known as the brorin) is expressed both in neural tissues in embryos and in neurons in the adult mouse brain and is involved in neurogenesis ( 43 ). In a recent study plasma EFNA4, CLM6, and VWC2 were negatively associated with general fluid cognitive ability in old individuals, an association that appeared to be mediated by brain volume ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Exposure to Mild Steel Welding and Changes in Serum Proteins With Putative Neurological Function—A Longitudinal Study

Gliga

Taj

Wahlberg

et al. 2020

Front. Public Health

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Welders are exposed to high levels of metal particles, consisting mainly of iron and manganese (Mn) oxide. Metal particles, especially those containing Mn can be neurotoxic. In this exploratory study, we evaluated associations between welding and expression of 87 putative neurology-related proteins in serum in a longitudinal approach. The study cohort from southern Sweden included welders working with mild steel ( n = 56) and controls ( n = 67), all male and non-smoking, which were sampled at two timepoints (T1, T2) 6-year apart. Observed associations in the longitudinal analysis (linear mixed models) were further evaluated (linear regression models) in another cross-sectional sample which included welders ( n = 102) and controls ( n = 89) who were sampled only once (T1 or T2). The median respirable dust levels for welders after adjusting for respiratory protection was at T1 0.6 (5–95 percentile: 0.2–4.2) and at T2 0.5 (0.1–1.8) mg/m 3 . The adjusted median respirable Mn concentration was at T2 0.049 mg/m 3 (0.003–0.314) with a Spearman correlation between adjusted respirable dust and respirable Mn of r S = 0.88. We identified five neurology-related proteins that were differentially expressed in welders vs. controls in the longitudinal sample, of which one (nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1; NMNAT1) was also differentially expressed in the cross-sectional sample. NMNAT1, an axon-protective protein linked to Alzheimers disease, was upregulated in welders compared with controls but no associations were discerned with degree of exposure (welders only: years welding, respirable dust, cumulative exposure). However, we identified five additional proteins that were associated with years welding (GCSF, EFNA4, CTSS, CLM6, VWC2; welders only) both in the longitudinal and in the cross-sectional samples. We also observed several neurology-related proteins that were associated with age and BMI. Our study indicates that low-to-moderate exposure to welding fumes is associated with changes in circulating levels of neurology-related proteins.

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“…THBS4 encodes a secreted extracellular-matrix glycoprotein necessary for appropriate neuronal migration in the mouse 40 and is elevated 6-fold in the human cortex compared with non-vocal learning primates 41 . Human EDA2R was recently identified as a top correlate of cognitive performance and brain size 42 ; it was also found in a human GWAS study to correlate with circulating estrogen and testosterone levels 43 . Rare mutations in human PHETA1 lead to Lowe oculocerebrorenal syndrome, the pathophysiology that includes seizures, mental retardation, and structural brain abnormalities 44,45 .…”

Section: Gene Drivers Of E2-treated Female Hvc Specializationmentioning

confidence: 98%

Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

Davenport

Choe²,

Matsunami

et al. 2021

Preprint

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Zebra finches are sexually dimorphic vocal learners. Males learn to sing by imitating mature conspecifics, but females do not. The lack of vocal learning in females is associated with anatomical differences in the neural circuits responsible for vocal learning, including the atrophy of several brain regions during development1. However, this atrophy can be prevented and song learning retained in females after pharmacological estrogen treatment2–4. Little is known about the genetic machinery controlling this sex and estrogen responsive song system development. To screen for drivers, we performed an unbiased analysis of transcriptomes from song control nuclei and surrounding motor regions in zebra finches of either sex treated with 17-β-estradiol or vehicle until sacrifice on day 30, when divergence between the sexes is anatomically apparent. Utilizing the newly assembled autosomes and sex chromosomes from the zebra finch Vertebrate Genomes Project assemblies5, we identified correlated gene modules that were associated to song nuclei in a sex and estradiol dependent manner. Female estradiol treated HVC, in the vocal learning circuit, acquired the smallest of the modular specializations observed in male HVC. This module was enriched for genes governing anatomical development, and it’s specilization was dispraportionately influenced by the expression of Z sex chromosome transcripts in HVC. We propose that vocal learning may be prevented in female zebra finches via the suppression of an estrogen inducible Z chromosome cis-acting regulatory element.

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Neurology-related protein biomarkers are associated with cognitive ability and brain volume in older age

Cited by 49 publications

References 63 publications

The plasma peptides of Alzheimer’s disease

The plasma peptides of Alzheimer’s disease

Exposure to Mild Steel Welding and Changes in Serum Proteins With Putative Neurological Function—A Longitudinal Study

Sex chromosome gene expression associated with vocal learning following hormonal manipulation in female zebra finches

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