TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

Stephanie M. Williams, Galam Khan, Brent T. Harris, John Ravits, Michael Sierks

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. Results: We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. Conclusions: These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker profile with potential to distinguish different TDP-43 pathologies.

Original languageEnglish (US)
Article number20
JournalBMC Neuroscience
Volume18
Issue number1
DOIs
StatePublished - Jan 25 2017

Fingerprint

Amyotrophic Lateral Sclerosis
Biomarkers
Proteins
Immunoglobulin Fragments
Brain
Pathology
Single-Chain Antibodies
Frontotemporal Dementia
Chromosomes, Human, Pair 9
Atomic Force Microscopy
Neurodegenerative Diseases
Bacteriophages
Open Reading Frames
Libraries
Enzyme-Linked Immunosorbent Assay

Keywords

  • Amyotrophic lateral sclerosis
  • Biomarker
  • Brain tissue
  • Plasma
  • ScFv
  • TDP-43 variants

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis. / Williams, Stephanie M.; Khan, Galam; Harris, Brent T.; Ravits, John; Sierks, Michael.

In: BMC Neuroscience, Vol. 18, No. 1, 20, 25.01.2017.

Research output: Contribution to journalArticle

Williams, Stephanie M. ; Khan, Galam ; Harris, Brent T. ; Ravits, John ; Sierks, Michael. / TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis. In: BMC Neuroscience. 2017 ; Vol. 18, No. 1.
@article{4ffd4e08ff4a4ab48231fd3699c2c8ce,
title = "TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis",
abstract = "Background: TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. Results: We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. Conclusions: These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker profile with potential to distinguish different TDP-43 pathologies.",
keywords = "Amyotrophic lateral sclerosis, Biomarker, Brain tissue, Plasma, ScFv, TDP-43 variants",
author = "Williams, {Stephanie M.} and Galam Khan and Harris, {Brent T.} and John Ravits and Michael Sierks",
year = "2017",
month = "1",
day = "25",
doi = "10.1186/s12868-017-0334-7",
language = "English (US)",
volume = "18",
journal = "BMC Neuroscience",
issn = "1471-2202",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis

AU - Williams, Stephanie M.

AU - Khan, Galam

AU - Harris, Brent T.

AU - Ravits, John

AU - Sierks, Michael

PY - 2017/1/25

Y1 - 2017/1/25

N2 - Background: TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. Results: We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. Conclusions: These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker profile with potential to distinguish different TDP-43 pathologies.

AB - Background: TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. Results: We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. Conclusions: These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker profile with potential to distinguish different TDP-43 pathologies.

KW - Amyotrophic lateral sclerosis

KW - Biomarker

KW - Brain tissue

KW - Plasma

KW - ScFv

KW - TDP-43 variants

UR - http://www.scopus.com/inward/record.url?scp=85010377960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010377960&partnerID=8YFLogxK

U2 - 10.1186/s12868-017-0334-7

DO - 10.1186/s12868-017-0334-7

M3 - Article

C2 - 28122516

AN - SCOPUS:85010377960

VL - 18

JO - BMC Neuroscience

JF - BMC Neuroscience

SN - 1471-2202

IS - 1

M1 - 20

ER -