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Single-cell Glycogenomics Deciphers Links Between Altered Transcriptional Regulation and Aberrant Glycosylation in Alzheimer's Disease

Matsui, Y.; Togayachi, A.; Sakamoto, K.; Angata, K.; Kadomatsu, K.; Nishihara, S.

2023-12-27 systems biology
10.1101/2023.12.25.573290 bioRxiv
Show abstract

Glycosylation is increasingly recognized as a potential therapeutic target in Alzheimers disease. In recent years, evidence of Alzheimers disease-specific glycoproteins has been established. However, the mechanisms underlying their dysregulation, including tissue- and cell-type specificity, are not fully understood. We aimed to explore the upstream regulators of aberrant glycosylation by integrating multiple data sources using a glycogenomics approach. We identified dysregulation of the glycosyltransferase PLOD3 in oligodendrocytes as an upstream regulator of cerebral vessels and found that it is involved in COL4A5 synthesis, which is strongly correlated with amyloid fiber formation. Furthermore, COL4A5 has been suggested to interact with astrocytes via extracellular matrix receptors as a ligand. This study suggests directions for new therapeutic strategies for Alzheimers disease targeting glycosyltransferases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/573290v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@14d608forg.highwire.dtl.DTLVardef@fe8352org.highwire.dtl.DTLVardef@15f8f77org.highwire.dtl.DTLVardef@c3ef28_HPS_FORMAT_FIGEXP M_FIG C_FIG

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The top 5 journals account for 50% of the predicted probability mass.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.