Dataset Information

A Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling

ABSTRACT: Benchmarking different LFQ-DIA approaches with traditional TMT-DDA for thermal proteome profiling.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: Matthias Trost

LAB HEAD: Prof Matthias Trost

PROVIDER: PXD040173 | Pride | 2023-10-24

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20220505_ALG_THP1TPP_TMTDDA_Pool1_F1.raw	Raw
	20220505_ALG_THP1TPP_TMTDDA_Pool1_F10.raw	Raw
	20220505_ALG_THP1TPP_TMTDDA_Pool1_F11.raw	Raw
	20220505_ALG_THP1TPP_TMTDDA_Pool1_F12.raw	Raw
	20220505_ALG_THP1TPP_TMTDDA_Pool1_F2.raw	Raw

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Publications

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling.

George Amy L AL Sidgwick Frances R FR Watt Jessica E JE Martin Mathew P MP Trost Matthias M Marín-Rubio José Luis JL Dueñas Maria Emilia ME

Journal of proteome research 20230713 8

Thermal proteome profiling (TPP) provides a powerful approach to studying proteome-wide interactions of small therapeutic molecules and their target and off-target proteins, complementing phenotypic-based drug screens. Detecting differences in thermal stability due to target engagement requires high quantitative accuracy and consistent detection. Isobaric tandem mass tags (TMTs) are used to multiplex samples and increase quantification precision in TPP analysis by data-dependent acquisition (DDA ...[more]

PMID: 37439223

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Project description:Background Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by language deficits due to severe temporal lobe degeneration. The consistent neuropathological diagnosis is FTD-TDP subtype C, with characteristic round TDP-43 protein inclusions in the dentate gyrus. Despite this striking clinicopathological concordance, the pathogenic mechanisms are largely unexplained forestalling the development of targeted therapeutics. Methods We carried out laser capture microdissection of the dentate gyrus of 15 SD patients and 17 non-demented controls, and assessed relative protein abundance changes by label-free quantitative mass spectrometry. To identify SD specific proteins, we compared our results to eight other FTD and Alzheimer’s disease (AD) proteomic datasets of cortical brain tissue, parallel with functional enrichment analyses and protein-protein interactions (PPI). Results Of the total 5,354 quantified proteins, 151 showed differential abundance (FDR<1%) in SD patients. Seventy-two proteins were previously found altered with the same directional change in at least one FTD/AD proteomic study, while 79 proteins were considered as showing potentially SD specific dysregulation. Functional enrichment indicated an overrepresentation of pathways related to the immune response, metabolic processes, and cell-junction assembly. PPI analysis highlighted a cluster of interacting proteins associated with adherens junction and cadherin binding– the cadherin-catenin complex. Multiple proteins in this complex showed strong and apparent specific upregulation in SD, including β-catenin (CTNNB1), γ-catenin (JUP), and N-cadherin (CDH2). Conclusions We discovered an increase of cell adhesion proteins in SD specifically constituting the cadherin-catenin complex at the synaptic membrane, essential for synaptic signaling. Although further validation is warranted, we anticipate that these findings will help unravel the disease processes underlying SD.