Sari, V. | bioRxiv Science

bioRxiv2026

Color-dependent foraging in C. elegans integrates chromoprotein photosensitization with bacterial metabolic cues

Animals rely on color to navigate complex environments, yet how eyeless organisms use chromatic information to guide food choice remains poorly understood. Here, we show that Caenorhabditis elegans exhibits robust color dependent foraging driven by microbial chromophores, preferentially consuming red while avoiding blue chromoprotein expressing bacteria across bacterial backgrounds and wild isolates. This discrimination persists in darkness and independently of photoreceptor, revealing a mechanism beyond canonical photoreception. Purified chromoproteins and bacterial metabolite fractions independently reproduce preference, demonstrating complementary chromatic and post ingestive metabolic cues. Mechanistically, blue chromoproteins generate singlet oxygen, producing oxidative stress and remodeling bacterial tryptophan and pterin metabolism, whereas red food promotes serotonin production and feeding-associated neuropeptide signaling. Disrupting serotonin biosynthesis or neuropeptide processing abolishes color preference. Together, our findings reveal a previously unrecognized, novel sensory strategy in which wavelength-selective pigment photochemistry transforms microbial color into metabolic information that is integrated through gut brain neuroendocrine signaling to guide foraging behavior in an eyeless animal.

molecular biology↗

bioRxiv2026

NPC1 deficiency engages a lysosome - genome - immune program linked to neurodegeneration and cellular aging signatures

Lysosomal dysfunction is a prominent feature of neurodegeneration and aging, yet how primary defects in lysosomal trafficking are converted into progressive cellular decline remains poorly understood. Niemann Pick disease type C (NPC), caused by impaired NPC1 dependent cholesterol export, provides a genetically defined model to address this question. Here, we show that NPC1 deficiency activates a lysosome, genome, immune axis linking cholesterol trafficking failure to neurodegeneration and hallmarks of cellular aging. In Npc1 mutant mice, NPC1 loss triggered DNA damage, neuroinflammation, microglial and astrocytic activation, Purkinje neuron degeneration, and motor dysfunction. Consistently, NPC patient-derived fibroblasts exhibited mitochondrial abnormalities and widespread DNA double-strand breaks. Genome-wide DNA break mapping and transcriptomic analyses revealed extensive genomic instability at regulatory regions, including enrichment of DNA breaks at transcription start sites and G quadruplex associated loci, accompanied by widespread transcriptional reprogramming, activation of innate immune pathways, disruption of fibroblast identity, and induction of cellular aging signatures. We further identify Fingolimod, an FDA approved sphingosine - 1 phosphate receptor modulator, as a potent modifier of this disease network. Fingolimod improved lysosomal cholesterol trafficking, increased LAMP1 abundance, attenuated STING associated inflammatory signaling, normalized mitochondrial function, reduced neuroinflammatory and neurodegenerative phenotypes in Npc1 mutant mice, and broadly shifted disease-associated transcriptional programs toward a healthier state. Extending these findings beyond NPC, Fingolimod improved age-associated phenotypes in C. elegans and prolonged lifespan in aged male mice. Together, these findings identify genome instability and chronic innate immune activation as major downstream consequences of lysosomal cholesterol trafficking failure and establish Fingolimod as a clinically actionable modulator of lysosomal dysfunction, neurodegeneration, and aging-related decline.

molecular biology↗