Motor Neurone Disease Association (Malaspina/Apr13/817–791). Wellcome
Trust support to a parallel study (Pathfinder Award, grant number 103208)

A Buchberger

A Chio

A Freund

A Jawaid

A Malaspina

Andrea Malaspina

AP Simopoulos

BR Brooks

C Margadant

C Pizzasegola

Caterina Bendotti

CH Lu

Ching-Hua Lu

CL Russell

D Baumer

D Cutuli

D Edbauer

D Gonzalez

D Karussis

D Moujalled

D Petrov

DR Howlett

EE Govek

Emanuela Leoni

F Endo

F Schmitt

F Yin

G Liu

G Nardo

Giovanni Nardo

H Zaid

HB van der Worp

Ian Pike

Irene Zubiri

JP Taylor

JS Bogan

JS Desgrosellier

JS Henkel

K Foley

K Houi

KI Gawlik

KV Kandror

L Lacomblez

Linda Greensmith

LM Ittner

M Bowerman

M Filareti

M Krauthausen

M Marino

M Rentzos

Malcolm Ward

Michael Bremang

MR Bronzuoli

MR Turner

MT Heneka

NJ Hoffman

Ozlem Yildiz

P Dibaj

P Newsholme

PH Gordon

Ping Yip

R Haas

R Pal

RA Medina

Rocco Adiutori

S Koncarevic

S Rossi

S Vadakkadath Meethal

S Victorelli

SE Leney

SJ Chinta

SR Pfohl

ST Ngo

Sun-Hwa Lee

TC Hornik

TE Finn

V Picher-Martel

V Rapisarda

Vikram Mitra

Vittoria Lombardi

Y Lee

Y Ovadya

Y Zhang

Molecular Neurodegeneration

Crossref

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

Figure S1. represents and scheme of the workflow followed to perform this study. Figure S2. shows the PCA before batch effect correction, Figure S3. shows enriched biological processes for the cross-sectional and longitudinal study. Table S1. shows the top regulated proteins in plasma from 1) fast versus slow progressing ALS patients at the late stage disease, early versus late time points for slow and fast progressing ALS patients and mouse model: cross sectional and longitudinal studies. Table S2. where the functional analysis of the animal model proteomic data are presented. Table S3. Presents the top regulated proteins in plasma from Wild type versus SOD1G93A transgenic mice at the pre-symptomatic and symptomatic stage of disease, for both genetic backgrounds under investigation. Table S4. contains the results for the functional analysis for the proteomic study comparing wild type versus transgenic ALS SOD1G93A mice. Table S5. Shows the proteomic data of the immunosenescence protein candidates selected for the re-test experiments. (DOCX 295 kb).

Irene Zubiri (449831)

Vittoria Lombardi (5944472)

Michael Bremang (5944475)

Vikram Mitra (543161)

Giovanni Nardo (202322)

Rocco Adiutori (558730)

Ching-Hua Lu (315782)

Emanuela Leoni (470520)

Ping Yip (191049)

Ozlem Yildiz (5944484)

Malcolm Ward (133933)

Linda Greensmith (252146)

Caterina Bendotti (202355)

Ian Pike (133930)

Andrea Malaspina (315789)

The Francis Crick Institute

Additional file 1: of Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

BACKGROUND: It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery. METHODS: We have applied TMTcalibrator™, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates. RESULTS: The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients. CONCLUSIONS: These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model

Zubiri, I

Lombardi, V

Bremang, M

Mitra, V

Nardo, G

Adiutori, R

Lu, C-H

Leoni, E

Yip, P

Yildiz, O

Ward, M

Greensmith, L

Bendotti, C

Pike, I

Malaspina, A

UCL Discovery

Queen Mary Research Online

Detailed protocols for Sample fractionation, LC-MS/MS analysis and peptide identification and quantification: methods are explained in more detail in this additional file. (PDF 14 kb

Additional file 2: of Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

contains all the raw data generated in the animal model analysis. (CSV 3617 kb

Additional file 4: of Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

Abstract Background It is unclear to what extent pre-clinical studies in genetically homogeneous animal models of amyotrophic lateral sclerosis (ALS), an invariably fatal neurodegenerative disorder, can be informative of human pathology. The disease modifying effects in animal models of most therapeutic compounds have not been reproduced in patients. To advance therapeutics in ALS, we need easily accessible disease biomarkers which can discriminate across the phenotypic variants observed in ALS patients and can bridge animal and human pathology. Peripheral blood mononuclear cells alterations reflect the rate of progression of the disease representing an ideal biological substrate for biomarkers discovery. Methods We have applied TMTcalibrator™, a novel tissue-enhanced bio fluid mass spectrometry technique, to study the plasma proteome in ALS, using peripheral blood mononuclear cells as tissue calibrator. We have tested slow and fast progressing SOD1G93A mouse models of ALS at a pre-symptomatic and symptomatic stage in parallel with fast and slow progressing ALS patients at an early and late stage of the disease. Immunoassays were used to retest the expression of relevant protein candidates. Results The biological features differentiating fast from slow progressing mouse model plasma proteomes were different from those identified in human pathology, with only processes encompassing membrane trafficking with translocation of GLUT4, innate immunity, acute phase response and cytoskeleton organization showing enrichment in both species. Biological processes associated with senescence, RNA processing, cell stress and metabolism, major histocompatibility complex-II linked immune-reactivity and apoptosis (early stage) were enriched specifically in fast progressing ALS patients. Immunodetection confirmed regulation of the immunosenescence markers Galectin-3, Integrin beta 3 and Transforming growth factor beta-1 in plasma from pre-symptomatic and symptomatic transgenic animals while Apolipoprotein E differential plasma expression provided a good separation between fast and slow progressing ALS patients. Conclusions These findings implicate immunosenescence and metabolism as novel targets for biomarkers and therapeutic discovery and suggest immunomodulation as an early intervention. The variance observed in the plasma proteomes may depend on different biological patterns of disease progression in human and animal model

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https://figshare.com/articles/Additional_file_4_of_Tissue-enhanced_plasma_proteomic_analysis_for_disease_stratification_in_amyotrophic_lateral_sclerosis/7313921

Tissue-enhanced plasma proteomic analysis for disease stratification in amyotrophic lateral sclerosis

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