Generation and characterization of monoclonal antibodies against pathologically phosphorylated TDP-43

Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we...

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Published in:PloS one 2024-04, Vol.19 (4), p.e0298080-e0298080
Main Authors: Castellanos Otero, Paula, Todd, Tiffany W, Shao, Wei, Jones, Caroline J, Huang, Kexin, Daughrity, Lillian M, Yue, Mei, Sheth, Udit, Gendron, Tania F, Prudencio, Mercedes, Oskarsson, Björn, Dickson, Dennis W, Petrucelli, Leonard, Zhang, Yong-Jie
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Analysis
Animals
Antibodies, Monoclonal
Biology and Life Sciences
Care and treatment
Diagnosis
DNA binding proteins
DNA-Binding Proteins - genetics
Dosage and administration
Frontotemporal Dementia - pathology
Genetic aspects
HEK293 Cells
Humans
Medicine and Health Sciences
Mice
Monoclonal antibodies
Neurophysiology
Research and Analysis Methods
TDP-43 Proteinopathies
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Summary:Inclusions containing TAR DNA binding protein 43 (TDP-43) are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). One of the disease-specific features of TDP-43 inclusions is the aberrant phosphorylation of TDP-43 at serines 409/410 (pS409/410). Here, we developed rabbit monoclonal antibodies (mAbs) that specifically detect pS409/410-TDP-43 in multiple model systems and FTD/ALS patient samples. Specifically, we identified three mAbs (26H10, 2E9 and 23A1) from spleen B cell clones that exhibit high specificity and sensitivity to pS409/410-TDP-43 peptides in an ELISA assay. Biochemical analyses revealed that pS409/410 of recombinant TDP-43 and of exogenous 25 kDa TDP-43 C-terminal fragments in cultured HEK293T cells are detected by all three mAbs. Moreover, the mAbs detect pS409/410-positive TDP-43 inclusions in the brains of FTD/ALS patients and mouse models of TDP-43 proteinopathy by immunohistochemistry. Our findings indicate that these mAbs are a valuable resource for investigating TDP-43 pathology both in vitro and in vivo.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0298080