[
International Worm Meeting,
2019]
Microbiota is known for its various effects on the human body with implications in chronic intestinal diseases, asthma and allergies. Emerging evidence is beginning to link the microbiome and dysbiosis to neurodegenerative disorders, including for Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). However, little is known about the beneficial effects of bacteria in age-dependent neurodegeneration. We partnered with Lallemand Health Solutions to develop assays using C. elegans to screen probiotic strains for their effects on various health and aging phenotypes. We identified a bacterial strain able to reduce motility deficits and neurodegeneration phenotypes in our C. elegans models of ALS, AD and HD. We used a combination of genetics and gene expression profiling to identify genes and pathways that are influenced by microbiota and are responsible for neuroprotection in our worm models. Our results implicate a novel mechanism responsible for this neuroprotection, involving mitochondrial b-oxidation. Moreover, we identified lipid dysequilibrium in our models of neurodegeneration. In summary, we provide new insight on impaired lipid metabolism in neurodegenerative disorders and how dietary intervention can restore lipid homeostasis and energy balance through mitochondrial b-oxidation, leading to neuroprotective effects. An update of our findings will be presented.
[
MicroPubl Biol,
2021]
Mutations in the human DNA/RNA binding protein FUS are associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration, including some aggressive and juvenile onset forms. Cytoplasmic inclusions of human FUS proteins are observed in various neurodegenerative disorders, such as Huntington's disease or spinocerebellar ataxia, suggesting that FUS proteinopathy may be a key player in neurodegeneration. To better understand the pathogenic mechanisms of FUS, we created single copy transgenic Caenorhabditis elegans strains expressing full-length, untagged human FUS in the worm's GABAergic neurons. These transgenic worms expressing human mutant FUS (mFUS) display the same ALS-associated phenotypes than our previous multiple copy transgenic model, including adult-onset age-dependent loss of motility, progressive paralysis and GABAergic neurodegeneration. These phenotypes are distinct from the transgenic worms expressing human wild-type FUS (wtFUS). We introduce here our C. elegans single copy transgenic for human mutant FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening.