Longitudinal Deep Multi-Omics Profiling in aCLN3^Δex7/8Minipig Model Reveals Novel Biomarker Signatures for Batten Disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 22, 2023

Abstract Development of therapies for CLN3 Batten disease, a rare pediatric lysosomal storage disorder, has been hindered by the lack etiological insights and translatable biomarkers to clinics. Here, we used deep multi-omics approach discover new using longitudinal serum samples from porcine model disease. Comprehensive metabolomics was combined with nanoparticle-based LC-MS-based proteomic profiling coupled TMTpro 18-plex generate quantitative data on 769 metabolites 2,634 proteins, collectively most exhaustive profile conducted model, which previously impossible due efficient proteome technologies compatible organisms. The presymptomatic disease state characterized elevations in glycerophosphodiester species proteases, while later timepoints were enriched involved immune cell activation sphingolipid metabolism. Cathepsin S, B, glycerophosphoinositol, glycerophosphoethanolamine captured large portion genotype-correlated variation between healthy diseased animals, suggesting that an index score based these analytes could have great utility clinic.

Язык: Английский

A CNC-Family Transcription Factor Nrf3 Coordinates the Melanogenesis Cascade Through Macropinocytosis and Autophagy Regulation

SSRN Electronic Journal, Год журнала: 2022, Номер unknown

Опубликована: Янв. 1, 2022

Melanin is a natural pigment produced from tyrosine in the melanosomes. The CNC-family transcription factor, Nrf3, expressed basal layer of epidermis, where melanocytes reside, although its melanogenic function unknown. Here, we show that Nrf3 coordinates melanogenesis through macropinocytosis and autophagy regulation. In response to forskolin, an extrinsic inducer melanin production, upregulates core gene circuit, containing Mitf, Tyr, Tyrp1, Pmel, Oca2. Furthermore, three autophagosome-related factors, Cln3, Ulk2, Gabarapl2, are identified as Nrf3-target genes contribute induction precursor uptake autophagosome formation for melanosome formation. parallel, prompts autolysosomal degradation melanocyte survival. Nrf3-mediated also activated by αMSH, intrinsic inducer, whereas it suppressed nelfinavir, HIV-1 protease inhibitor. These results reveal impacts nelfinavir cascade skin hyperpigmentation therapy.

Язык: Английский