Labarre, Audrey et al. (2021) MicroPubl Biol

Parker, Alex, Tossing, Gilles, Doyle, James J, Labarre, Audrey, Maios, Claudia

[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.

Labarre, Audrey et al. (2019) International Worm Meeting "Probiotic-mediated suppression of age-related neurodegeneration."

Parker, J Alex, Tossing, Gilles, Labarre, Audrey, Guitard, Ericka

[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.

Labarre, Audrey et al. (2017) International Worm Meeting "Modulation of Gut Microbiota Rescues Paralysis and Neurodegeneration in C. elegans ALS Models."

Labarre, Audrey, Parker, J Alex

[International Worm Meeting, 2017]

Microbiota is known for its various effects on the human body with implications in chronic intestinal diseases, asthma and allergies. Some evidence is beginning to link microbiota to neurodegeneration. Moreover, microbiota is known for its impact on serotoninergic neurons, especially in serotonin biosynthesis regulation, and these neurons are the most vulnerable in ALS. However, there is no available date for ALS. In 2014 we partnered with Lallemand Health Solutions to develop an assay in C. elegans to screen probiotic strains for their effects on fat accumulation. We were curious if these probiotics had additional effects so we tested them in a variety of assays, including lifespan, stress resistance, as well as in our worm ALS models. We were surprised to discover that two strains suppressed motility defects and motor neuron degeneration in our C. elegans models of ALS. But what accounts for this neuroprotective effect? 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 worms. So far, we demonstrated that our C. elegans ALS models, when fed with specific probiotics, show a rescue of neurodegeneration and adult-onset age-dependant paralysis. The neuroprotection provided by these probiotics are not dependant on classic metabolic/stress resistance pathways in C. elegans, like daf-16 and hsf-1, but seems to be linked to fat metabolism. Finally, these findings may confirm a link between microbiota and ALS, and can lead the way to future therapies perhaps through modulation of the intestinal environment.

Labarre, Audrey et al. (2015) International Worm Meeting "Single copy mutant TDP-43 and FUS transgenics cause age-dependent paralysis and neurodegeneration in C. elegans."

Maios, Claudia, Veriepe, Julie, Labarre, Audrey, Parker, J Alex

[International Worm Meeting, 2015]

Mutations in the DNA/RNA binding proteins TDP-43 and FUS are associated with amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder causing the loss of motor neurons. Moreover, cytoplasmic accumulations of wild type TDP-43 and FUS are observed in an important number of late-onset diseases suggesting that TDP-43 and FUS proteinopathies may contribute to multiple neurodegenerative diseases. Nevertheless, there is still a lack in understanding mechanisms of TDP-43 and FUS toxicity and due to the implication of these proteinopathies in various diseases, the development of novel therapeutic avenues is needed more than ever. Previous work done in the lab showed that worms expressing full-length, untagged human multiple copies of TDP-43 and FUS in their GABAergic motor neurons have adult-onset, age-dependent loss of motility, progressive paralysis and neuronal degeneration that is distinct from wild type alleles. With the aim of developing a more accurate model, we created single copy transgenic worms expressing human TDP-43 and FUS in GABAergic motor neurons. Our TDP-43 and FUS worms show motility defects leading to age-dependant paralysis and neurodegeneration in the GABAergic motor neurons comparable to the previous model. Thus, single copy mutation seems to be efficient to cause the neurodegeneration phenotype associated with ALS in C. elegans. This new model may be used for rapid genetic and pharmacological suppressor screening, leading to the discovery of new therapeutic avenues in neurodegenerative disorders associated with TDP-43 and FUS proteinopathies.

Doyle, James J. et al. (2019) International Worm Meeting "Muscle degeneration precedes neurodegeneration in a C. elegans models of spinal muscular atrophy."

Doyle, James J., Maios, Claudia, Parker, J. Alex, Patten, Shunmoogum, Vrancx, Celine, Labarre, Audrey

[International Worm Meeting, 2019]

Spinal muscular atrophy is (SMA) is a devastating, autosomal recessive neuromuscular disease resulting in muscle atrophy and neurodegeneration, and it is the leading genetic cause of infant death. SMA arises when there are homozygous deletion mutations in the human SMN1 gene, leading to a decrease in corresponding SMN1 protein. Although SMN1 is expressed across multiple tissue types, much of the previous research into SMA focused on the neuronal aspect of the disease, overlooking many of the potential non-neuronal aspects of the disease. Therefore, we sought to address this gap in knowledge by modeling SMA in the nematode Caenorhabditis elegans. We used a previously uncharacterized allele which resulted in the onset of mild SMA-like phenotypes allowing us to monitor the onset of phenotypes at different stages. We observed that these mutant animals recapitulated many key features of the human disease, and most importantly, we observed that muscle dysfunction precedes neurodegeneration. Furthermore, we tested the therapeutic efficacy of targeting endoplasmic reticulum (ER) stress in non-neuronal cells and found it to be more effective than targeting ER stress in neuronal cells. We also found that the most potent therapeutic potential came from a combination of ER- and neuromuscular junction (NMJ)-targeting drugs. Together, our results suggest an important non-neuronal component of SMA pathology and highlights new considerations for therapeutic intervention.