Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants
Abstract Background Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pat...
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doaj-ee96b511bb27467ca60bc2febe2967582020-11-25T03:02:40ZengBMCBMC Neuroscience1471-22022020-09-0121111110.1186/s12868-020-00586-0Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variantsLalitha Venkataraman0Ping He1Galam Khan2Brent T. Harris3Michael R. Sierks4School of Life Sciences, Arizona State UniversityChemical Engineering, School for Engineering, Matter, Transport and Energy, Arizona State UniversityDepartments of Neurology, Georgetown University Medical CenterDepartments of Neurology, Georgetown University Medical CenterChemical Engineering, School for Engineering, Matter, Transport and Energy, Arizona State UniversityAbstract Background Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases. It plays a role in transcription, translation and serves as a shuttle between the nucleus and cytoplasm. Prior to its aggregation, TDP-43 exists as polyubiquitinated, hyperphosphorylated C-terminal fragments that correlate well with FTD disease progression. Because of the importance of TDP-43 in these diseases, reagents that can selectively recognize specific toxic TDP variants associated with onset and progression of FTD can be effective diagnostic and therapeutic tools. Results We utilized a novel atomic force microscopy (AFM) based biopanning protocol to isolate single chain variable fragments (scFvs) from a phage display library that selectively bind TDP variants present in human FTD but not cognitively normal age matched brain tissue. We then used the scFvs (FTD-TDP1 through 5) to probe post-mortem brain tissue and sera samples for the presence of FTD related TDP variants. The scFvs readily selected the FTD tissue and sera samples over age matched controls. The scFvs were used in immunohistochemical analysis of FTD and control brain slices where the reagents showed strong staining with TDP in FTD brain tissue slice. FTD-TDP1, FTD-TDP2, FTD-TDP4 and FTD-TDP5 all protected neuronal cells against FTD TDP induced toxicity suggesting potential therapeutic value. Conclusions These results show existence of different disease specific TDP variants in FTD individuals. We have identified a panel of scFvs capable of recognizing these disease specific TDP variants in postmortem FTD tissue and sera samples over age matched controls and can thus serve as a biomarker tool.http://link.springer.com/article/10.1186/s12868-020-00586-0Frontotemporal dementiaTDP-43 variantsscFvBiomarkerBrain tissueSera |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lalitha Venkataraman Ping He Galam Khan Brent T. Harris Michael R. Sierks |
spellingShingle |
Lalitha Venkataraman Ping He Galam Khan Brent T. Harris Michael R. Sierks Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants BMC Neuroscience Frontotemporal dementia TDP-43 variants scFv Biomarker Brain tissue Sera |
author_facet |
Lalitha Venkataraman Ping He Galam Khan Brent T. Harris Michael R. Sierks |
author_sort |
Lalitha Venkataraman |
title |
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants |
title_short |
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants |
title_full |
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants |
title_fullStr |
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants |
title_full_unstemmed |
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants |
title_sort |
isolation and characterization of antibody fragments selective for human ftd brain derived tdp-43 variants |
publisher |
BMC |
series |
BMC Neuroscience |
issn |
1471-2202 |
publishDate |
2020-09-01 |
description |
Abstract Background Frontotemporal dementia (FTD) is the second leading cause of early onset dementia following Alzheimer’s disease. It involves atrophy of the frontal and temporal regions of the brain affecting language, memory, and behavior. Transactive response DNA-binding protein 43 (TDP-43) pathology is found in most FTD and ALS cases. It plays a role in transcription, translation and serves as a shuttle between the nucleus and cytoplasm. Prior to its aggregation, TDP-43 exists as polyubiquitinated, hyperphosphorylated C-terminal fragments that correlate well with FTD disease progression. Because of the importance of TDP-43 in these diseases, reagents that can selectively recognize specific toxic TDP variants associated with onset and progression of FTD can be effective diagnostic and therapeutic tools. Results We utilized a novel atomic force microscopy (AFM) based biopanning protocol to isolate single chain variable fragments (scFvs) from a phage display library that selectively bind TDP variants present in human FTD but not cognitively normal age matched brain tissue. We then used the scFvs (FTD-TDP1 through 5) to probe post-mortem brain tissue and sera samples for the presence of FTD related TDP variants. The scFvs readily selected the FTD tissue and sera samples over age matched controls. The scFvs were used in immunohistochemical analysis of FTD and control brain slices where the reagents showed strong staining with TDP in FTD brain tissue slice. FTD-TDP1, FTD-TDP2, FTD-TDP4 and FTD-TDP5 all protected neuronal cells against FTD TDP induced toxicity suggesting potential therapeutic value. Conclusions These results show existence of different disease specific TDP variants in FTD individuals. We have identified a panel of scFvs capable of recognizing these disease specific TDP variants in postmortem FTD tissue and sera samples over age matched controls and can thus serve as a biomarker tool. |
topic |
Frontotemporal dementia TDP-43 variants scFv Biomarker Brain tissue Sera |
url |
http://link.springer.com/article/10.1186/s12868-020-00586-0 |
work_keys_str_mv |
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