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Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient

ABSTRACT: Transthyretin-derived amyloidosis (ATTR) is a degenerative, systemic disease characterized by transthyretin fibril deposition in organs like the heart, kidneys, liver, and skin. We report the first cryo-EM structure of transthyretin fibrils isolated from skin tissue of a living patient with a rare genetic mutation (ATTRv F64S). The structure adopts a highly conserved fold previously observed in other ATTR fibrils from different tissues or genetic variants. Mass spectrometry was used to identify common post-translational modifications. The structural consistency between ATTR filaments validates non-invasive skin biopsy as a diagnostic tool.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

DISEASE(S): Transthyretin Amyloidosis

SUBMITTER: Matteo Pecoraro

LAB HEAD: Andreas Boland

PROVIDER: PXD065685 | Pride | 2025-11-03

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20231005_MP110_ElVa_SA_Skin_D_477_2022_Slot1-37_1_225.d.zip	Other
	20250409_MP220_ElVa_SA_Ankle_F84S_4024.d.zip	Other
	20250409_MP220_ElVa_SA_Thigh_F84S_4026.d.zip	Other
	Fibrils_acetylation_search.zip	Other
	Fibrils_methylation_search.zip	Other

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Project description:Herein we demonstrate the efficacy of an unbiased proteomics screening approach for studying protein expression changes in the KC-Tie2 psoriasis mouse model, identifying multiple protein expression changes in the mouse and validating these changes in human psoriasis. KC-Tie2 mouse skin samples (n=3) were compared with littermate controls (n=3) using gel-based fractionation followed by label-free protein expression analysis. 5482 peptides mapping to 1281 proteins were identified and quantitated: 105 proteins exhibited fold-changes ≥2.0 including: stefin A1 (average fold change of 342.4 and an average P = 0.0082; cystatin A, human orthologue); slc25a5 (average fold change of 46.2 and an average P = 0.0318); serpinb3b (average fold change of 35.6 and an average P = 0.0345; serpinB1, human orthologue); and kallikrein related peptidase 6 (average fold change of 4.7 and an average P = 0.2474; KLK6). We independently confirmed mouse gene expression-based increases of selected genes including serpinb3b (17.4-fold, P < 0.0001), KLK6 (9.0-fold, P = 0.002), stefin A1 (7.3-fold; P < 0.001) and slc25A5 (1.5-fold; P = 0.05) using qRT-PCR on a second cohort of animals (n=8). Parallel LC/MS/MS analyses on these same samples verified protein-level increases of 1.3-fold (slc25a5; P < 0.05), 29,000-fold (stefinA1; P < 0.01), 322-fold (KLK6; P < 0.0001) between KC-Tie2 and control mice. To underscore the utility and translatability of our combined approach, we analyzed gene and protein expression levels in psoriasis patient skin and primary keratinocytes vs. healthy controls. Increases in gene expression for slc25a5 (1.8-fold), cystatin A (3.0-fold), KLK6 (5.8-fold) and serpinB1 (76-fold; all P < 0.05) were observed between healthy controls and involved lesional psoriasis skin and primary psoriasis keratinocytes. Moreover slc25a5, cystatin A, KLK6 and serpinB1 protein were all increased in lesional psoriasis skin compared to normal skin. These results highlight the usefulness of preclinical disease models using readily-available mouse skin and demonstrate the utility of proteomic approaches for identifying novel peptides/proteins that are differentially regulated in psoriasis that could serve as sources of auto-antigens or provide novel therapeutic targets for the development of new anti-psoriatic treatments.

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Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient

Dataset's files

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