Biology subjects

Waghmare, S. G.

Publications and source records attributed to Waghmare, S. G..

3 recordsLinked to original sources

bioRxiv2026

Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes in Caenorhabditis elegans Identifies Regulators of Neuronal Aging

BackgroundGenome-wide studies in late-onset Alzheimers disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis in vivo remains challenging. MethodsUsing Caenorhabditis elegans as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs: ABI3/abi-1, B4GALT3/bre-4, CCDC6/T09B9.4, CLPTM1 (two homologs C36B7.6 and R166.2), CNN2/cpn-2, DMWD/wdr-20, ECHDC3/ech-2, MADD/aex-3, NCK2/nck-1, RABEP1/rabn-5, RIN3/rin-1, SLC39A13/zipt-13, TRAM1/tram-1, and USP6NL/tbc-17. We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory. ResultsLifespan was unaffected by most knockdowns, and only nck-1 and tbc-17 shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of aex-3, C36B7.6, cpn-2, ech-2, rabn-5, rin-1, T09B9.4, and zipt-13 attenuated late-life PVD degeneration, whereas R166.2 and tram-1 accelerated early PVD aging. Only two genes affected PLM aging: R166.2 knockdown exacerbated degeneration, while tbc-17 knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons, tbc-17 knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays, ech-2 knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with A{beta}-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human A{beta}1-42 panneuronally. In this model, A{beta} expression accelerated age-dependent PVD degeneration, whereas ech-2 knockdown abolished this A{beta}-induced effect. ConclusionsOur findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging in vivo in a neuron-class-selective manner, often dissociable from organismal longevity. This C. elegans framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.

neuroscience↗

bioRxiv2026

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

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.

neuroscience↗

bioRxiv2024

Fertilization by short-term stored sperm alters DNA methylation patterns in common carp (Cyprinus carpio) embryos at single-base resolution

Short-term storage of sperm in vitro is widely used for artificial fertilization in aquaculture. It has been shown that short-term storage affects sperm motility characteristics, resulting in diminished fertility. However, the detrimental effects of short-term sperm storage on embryos development have remained largely unexplored in single-base methylome resolution. The main aim of the present study was to investigate DNA methylation in the offspring of common carp (Cyprinus carpio) derived from short-term stored sperm. Sperm were stored in artificial seminal plasma on ice (0-2{degrees}C) for 0, 3 and 6 days in vitro, fertilization was performed using oocytes from a single female, and embryos were collected at the mid-blastula stage. Sperm and embryo DNA was extracted, analysed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) and whole genome bisulfite sequencing (WGBS). DNA methylation was then assessed. Sperm storage showed negative effects on motility, viability and DNA integrity, but had no effect on global DNA methylation of spermatozoa and resulting embryos. Results from the WGBS showed that methylation of 3313 genes was affected in the embryos fertilized with the 6-day-stored sperm, and the differentially methylated regions (DMRs) identified were mainly involved in cell adhesion, calcium, mitogen-activated protein kinase and adrenergic signalling, melanogenesis, metabolism and RNA transport. Such results suggest that prolongation of storage time may have certain impacts on embryonic development. These initial results provide valuable information for future consideration of the DNA methylome in embryos generated from short-term stored sperm, which is widely used for genetic management of broodstock in aquaculture.

molecular biology↗