Biology subjects

Mor, D. E.

Publications and source records attributed to Mor, D. E..

5 recordsLinked to original sources

bioRxiv2024

Gut microbiome species Levilactobacillus brevis regulates reproductive fitness in C. elegans

The human gut microbiome has attracted considerable attention in recent years due to its broad impact on various physiological processes; however, the mechanisms underlying host-microbiota interactions are not fully understood. In particular, direct causal relationships between specific species and host health outcomes remain to be established. Here we examined the effects of human gut microbiome species Levilactobacillus brevis (L. brevis) on host health using C. elegans and found that L. brevis feeding caused significant reproductive dysfunction, including severe egg retention leading to fewer eggs laid, and abnormal egg morphologies. These effects were associated with impaired serotonin signaling in hermaphrodite-specific neurons (HSNs), which regulate egg-laying, while vulval muscle function remained intact. Progeny from L. brevis-fed worms exhibited reduced viability and delayed development, suggesting an overall reduction in C. elegans reproductive fitness. Our findings align with emerging evidence linking gut dysbiosis to reproductive health disorders in humans, and underscore the need to explore specific roles of individual gut microbiota in host health and physiology. Our work also highlights the utility of C. elegans as a model for studying the complex interactions between the microbiome and the host.

microbiology↗

bioRxiv2021

α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

Parkinsons disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of -synuclein protein. Growing evidence suggests that -synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain -synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with -synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human -synuclein expressed in the host. PFF acceleration of -synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with -synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived -synuclein spreading and propagation of disease.

neuroscience↗

bioRxiv2021

GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson's disease

BackgroundParkinsons disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are unknown, limiting the development of therapies directed at disease-relevant molecular targets. C. elegans is a genetically tractable model system that can be used to disentangle disease mechanisms in complex diseases such as PD. Such mechanisms can be studied combining high-throughput molecular profiling technologies such as transcriptomics and metabolomics. However, the integrative analysis of multi-omics data in order to unravel disease mechanisms is a challenging task without advanced bioinformatics training. Galaxy, a widely-used resource for enabling bioinformatics analysis by the broad scientific community, has poor representation of multi-omics integration pipelines. ResultsWe present the integrative analysis of gene expression and metabolite levels of a C. elegans PD model using GAIT-GM, a new Galaxy tool for multi-omics data analysis. Using GAIT-GM, we discovered an association between branched-chain amino acid metabolism and cholinergic neurons in the C. elegans PD model. An independent follow-up experiment uncovered cholinergic neurodegeneration in the C. elegans model that is consistent with cholinergic cell loss observed in PD. ConclusionGAIT-GM is an easy to use Galaxy-based tool for generating novel testable hypotheses of disease mechanisms involving gene-metabolite relationships.

neuroscience↗

bioRxiv2020

Metabolic defects cause hyperactive mitochondria and Parkinson disease-like traits

Metabolic dysfunction is a facet of many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood1. We recently discovered a potential causal link between the branched-chain amino acid transferase, BCAT-1, and the neurodegenerative movement disorder, Parkinsons disease (PD)2. Knockdown of C. elegans bcat-1 recapitulates PD-like features, including progressive motor deficits and neurodegeneration with age2. Using transcriptomic, metabolomic, and imaging approaches, we show that bcat-1 knockdown increases mitochondrial activity and induces oxidative damage in neurons through mTOR-independent mechanisms. We recently developed a high-throughput screening platform to identify drugs that may be repurposed for PD, and found that metformin, the leading type 2 diabetes medication, significantly improves motor function in bcat-1(RNAi) worms3. Late-in-life metformin treatment restores normal mitochondrial activity levels and protects against bcat-1-associated neurodegeneration. Our results suggest that PD may originate as a metabolic disorder, and highlight metformin as a promising new drug candidate for PD treatment.

neuroscience↗

bioRxiv2020

High-throughput behavioral screen in C. elegans reveals novel Parkinson disease drug candidates

We recently linked branched-chain amino acid transferase 1 (BCAT1) with the movement disorder Parkinsons disease (PD), and found that reduction of C. elegans bcat-1 causes abnormal spasm-like curling behavior with age. Here, we report the development of a high-throughput automated curling assay and its application to the discovery of new potential PD therapeutics. Four FDA-approved drugs were identified as candidates for late-in-life intervention, with metformin showing the greatest promise for repurposing to PD.

neuroscience↗