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TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies.

Goossens J, Vanmechelen E, Trojanowski JQ, Lee VM, Van Broeckhoven C, van der Zee J, Engelborghs S - Acta Neuropathol Commun (2015)

Bottom Line: After quality assessment, antibody characteristics and related outcomes were extracted.A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once.These antibodies can be used in future studies of TDP-43 proteinopathies.

View Article: PubMed Central - PubMed

ABSTRACT
Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer's disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.

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Selected antibodies mapped to the TDP-43 protein. Antibodies from the primary selection are marked in black, antibodies from the secondary selection are marked in grey. Asterisks indicate phosphorylation-dependent antibodies. Bold italic antibodies are those which are considered “standard” when studying TDP-43. NLS = nuclear localization signal, NES = nuclear export signal, RRM = RNA-recognition motive.
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Fig1: Selected antibodies mapped to the TDP-43 protein. Antibodies from the primary selection are marked in black, antibodies from the secondary selection are marked in grey. Asterisks indicate phosphorylation-dependent antibodies. Bold italic antibodies are those which are considered “standard” when studying TDP-43. NLS = nuclear localization signal, NES = nuclear export signal, RRM = RNA-recognition motive.

Mentions: While mutations in a specific gene induce an associated molecular pathology, no strict relationship exists between clinical FTLD subtype and underlying proteinopathy [15,23]. Indeed, clinical symptoms rather reflect affected brain regions, which is especially exemplified in the heterogeneity of clinical FTLD. Moreover, it should be noted that up to 25% of clinical FTLD is actually due to atypical presentation of AD pathology [14,24]. The two-way clinicopathological association between FTLD(−TDP) and AD shows there is an urgent need for biomarkers that allow early and differential diagnosis of FTLD. A promising approach is quantification of disease-specific biochemical markers present in biofluids (cerebrospinal fluid (CSF) and blood) [23]. At present, well-characterized and validated diagnostic markers specific to FTLD pathology do not exist, with the exception of decreased progranulin concentrations for GRN mutation-related FTLD, a subgroup of FTLD-TDP [25,26]. A high-ranking candidate to become a biomarker for all FTLD-TDP patients is TDP-43 itself. Because of low absolute levels, quantitative analysis of TDP-43 in biofluids will demand a very sensitive immunoassay, preferably specific for pathological TDP-43 [27]. The TDP-43 protein comprises two RNA-recognition motives (RRM1-&2) and a glycine-rich C-terminal domain (Figure 1) [17,28]. Pathological aggregation of TDP-43 is regulated by both N-terminal and C-terminal regions, but also includes modifications like truncation, ubiquitination and phosphorylation [16,29-32]. Reported truncation sites are located inside the RRM2 and include Arg208, Asp218 and Asp247 [33-35] while major phosphorylation sites are serine residues located near the C-terminal end of TDP-43 [32,36].Figure 1


TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies.

Goossens J, Vanmechelen E, Trojanowski JQ, Lee VM, Van Broeckhoven C, van der Zee J, Engelborghs S - Acta Neuropathol Commun (2015)

Selected antibodies mapped to the TDP-43 protein. Antibodies from the primary selection are marked in black, antibodies from the secondary selection are marked in grey. Asterisks indicate phosphorylation-dependent antibodies. Bold italic antibodies are those which are considered “standard” when studying TDP-43. NLS = nuclear localization signal, NES = nuclear export signal, RRM = RNA-recognition motive.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4380254&req=5

Fig1: Selected antibodies mapped to the TDP-43 protein. Antibodies from the primary selection are marked in black, antibodies from the secondary selection are marked in grey. Asterisks indicate phosphorylation-dependent antibodies. Bold italic antibodies are those which are considered “standard” when studying TDP-43. NLS = nuclear localization signal, NES = nuclear export signal, RRM = RNA-recognition motive.
Mentions: While mutations in a specific gene induce an associated molecular pathology, no strict relationship exists between clinical FTLD subtype and underlying proteinopathy [15,23]. Indeed, clinical symptoms rather reflect affected brain regions, which is especially exemplified in the heterogeneity of clinical FTLD. Moreover, it should be noted that up to 25% of clinical FTLD is actually due to atypical presentation of AD pathology [14,24]. The two-way clinicopathological association between FTLD(−TDP) and AD shows there is an urgent need for biomarkers that allow early and differential diagnosis of FTLD. A promising approach is quantification of disease-specific biochemical markers present in biofluids (cerebrospinal fluid (CSF) and blood) [23]. At present, well-characterized and validated diagnostic markers specific to FTLD pathology do not exist, with the exception of decreased progranulin concentrations for GRN mutation-related FTLD, a subgroup of FTLD-TDP [25,26]. A high-ranking candidate to become a biomarker for all FTLD-TDP patients is TDP-43 itself. Because of low absolute levels, quantitative analysis of TDP-43 in biofluids will demand a very sensitive immunoassay, preferably specific for pathological TDP-43 [27]. The TDP-43 protein comprises two RNA-recognition motives (RRM1-&2) and a glycine-rich C-terminal domain (Figure 1) [17,28]. Pathological aggregation of TDP-43 is regulated by both N-terminal and C-terminal regions, but also includes modifications like truncation, ubiquitination and phosphorylation [16,29-32]. Reported truncation sites are located inside the RRM2 and include Arg208, Asp218 and Asp247 [33-35] while major phosphorylation sites are serine residues located near the C-terminal end of TDP-43 [32,36].Figure 1

Bottom Line: After quality assessment, antibody characteristics and related outcomes were extracted.A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once.These antibodies can be used in future studies of TDP-43 proteinopathies.

View Article: PubMed Central - PubMed

ABSTRACT
Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer's disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.

Show MeSH
Related in: MedlinePlus