NLP-12/Cholecystokinin signaling stabilizes sensory dendritic structure and protects neuronal healthspan in Caenorhabditis elegans

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ID: 338614
2026
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Abstract
Aging selectively degrades neuronal structure and function, yet the signals that actively preserve neuronal integrity over adult life remain incompletely defined. In Caenorhabditis elegans, the PVD sensory neuron develops progressive excessive higher-order dendritic branching during normal aging that correlates with declines in proprioceptive locomotion. Using this system as a quantitative in vivo readout of neuronal healthspan, we identify the cholecystokinin-like neuropeptide NLP-12 as a protective signal that preserves PVD homeostasis across adulthood. nlp-12 loss-of-function animals show early-onset excessive branching and earlier declines in proprioceptive function, whereas nlp-12 overexpression attenuates excessive branching in aged adults without extending lifespan, indicating a neuron-focused effect on healthspan. Longitudinal analysis of an NLP-12::mKate reporter reveals age-related reduction in extracellular delivery of NLP-12 and increased retention in the soma of the DVA interneuron, where nlp-12 is predominantly expressed. Consistent with a requirement for secretory trafficking, disrupting the NLP-12 signal peptide abolishes the rescue effects of wild-type nlp-12 reintroduction in nlp-12 mutants. Additionally, chemogenetic silencing of DVA during adulthood similarly accelerates excessive PVD branching, supporting an ongoing requirement for secreted DVA-derived NLP-12. Receptor genetics further show that both cholecystokinin receptor homologs, CKR-1 and CKR-2, are required downstream of NLP-12-mediated neuroprotection during aging. Finally, human cholecystokinin rescues PVD branching and partially improves proprioceptive patterning in nlp-12 mutants, supporting functional conservation. Together, these findings define conserved cholecystokinin-like neuropeptide signaling as an adult maintenance mechanism that buffers age-associated decline in neuronal resilience.
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Authors Meera M. Krishna, Swapnil G. Waghmare, Gabriel P. Phillips, Emily C. Maccoux, Tania Shaik, E Lezi
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Journal current genetics
Year 2026
DOI
10.1093/genetics/iyag315
URL
https://doi.org/10.1093/genetics/iyag315
Keywords Keywords not found

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