Agyal, N. | Search bioRxiv

bioRxiv2026

Identification of conserved age-associated aggregation-prone proteins for natural molecule targeting during aging in Caenorhabditis elegans

Aging is associated with proteome remodelling and progressive accumulation of insoluble proteins. Identifying age-enriched proteins that undergo aggregation and evaluating compounds capable of modulating their behaviour may provide insights into interventions that promote healthy aging. Here, we report a proteome-guided strategy to identify age-associated aggregation-prone proteins and evaluate phytochemicals targeting conserved proteins in Caenorhabditis elegans. We identified proteins whose abundance increased more than four-fold in aged worms compared with young worms, many of which also accumulated in the age-associated insoluble proteome, and subsequently identified their human orthologs for comparative analysis. Based on biological relevance, structural conservation, and availability of high-confidence structural models, glutamine-fructose-6-phosphate aminotransferase-2 (GFAT-2) was selected for molecular docking. Screening of fifteen phytochemicals against C. elegans GFAT-2 and its human ortholog GFPT1 identified quercetin as the strongest predicted binder, exhibiting conserved interactions with both proteins. However, treatment of worms with quercetin did not significantly alter global protein insolubility during aging. This may reflect its ability to modulate inappropriate protein-protein interactions without substantially affecting the overall aggregation burden. These findings underscore the need for experimental validation of favourable in silico docking predictions. More broadly, this study provides a proteome-guided framework for prioritizing age-associated aggregation-prone proteins as candidate therapeutic targets for preserving proteostasis during aging.

biochemistry↗

bioRxiv2026

Lessons learned from manual curation of thousands of gene models in the nematode Pristionchus pacificus

Continuous developments in sequencing technologies have led to the generation of chromosome-scale genome assemblies across the whole tree of life, but our ability to annotate genomes has lacked behind. One major problem consists in the fact that typically not all genes are expressed at detectable levels at any given life stage or environment. Therefore, available transcriptome data needs to be complemented by gene prediction programs and protein homology evidence. However, how to optimally combine these different data types is not well understood. Here, we present a case study, where we community curated gene annotations of the Pristionchus pacificus strain RSC011. By incorporation of new Iso-seq and RNA-seq data and genome-wide screening, we identified and corrected more than 7,500 ([~]24%) gene models. While the improved gene annotation for the RSC011 strain will be useful for the P. pacificus community, our study reveals several gene annotation problems that may affect data from other species. Among these, we identified assembly errors, artificial transcript fusions resulting from overlapping genes and polycistronic RNAs, falsely called open reading frames, and error propagation based on homology data as frequent sources of gene annotation errors. Thus, our findings may be helpful in guiding future efforts to annotate genomes across different taxonomic groups.

genomics↗