Study of microbial dietary supplementation and lipid dysregulation in neurodegeneration models

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease sharing pathological pathways with frontotemporal dementia (FTD). It is characterized by the selective degeneration of lower and upper motor neurons in the spinal cord and cerebral cortex. Over the last 25 years, more than 20 genes have been associated with these diseases, including FUS, C9ORF72 and TARDBP. Despite over a century of medical investigation, the links between pathology, disease stage and cellular mechanisms are still unclear, but may be multifactorial involving unresolved gene-environment interactions. While ALS is primarily considered a central nervous system disease, emerging evidence suggests that peripheral signals, including those from the gastrointestinal tract and gut microbiota, may be involved in ALS progression. Over the last year, new evidence showed perturbations in microbiota (called dysbiosis), mitochondrial bioenergetics, and in lipid composition in ALS. However, there is a considerable lack of understanding of the effect of these perturbations in ALS pathogenesis. Interestingly, dysbiosis has also been linked to other neurological conditions like Alzheimer’s disease (AD) and Huntington’s disease (HD). Using the model organism Caenorhabditis elegans, we discovered a probiotic bacterial strain, Lacticaseibacillus rhamnosus HA-114, with neuroprotective properties in models of ALS and HD.  In the first part of this thesis, we demonstrated that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains, and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are key fatty acid metabolism and mitochondrial β-oxidation genes. Moreover, L. rhamnosus HA-114 delayed disease onset and suppressed motor neuron degeneration in an aggressive mouse model of ALS. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial β-oxidation.  In the second part of this thesis, we used C. elegans and characterized the CHCHD10 orthologue har-1, in a number of behavioral assays, to learn more about the biological role of this gene and its implication in ALS-FTD pathogenesis. CHCHD10 is a widely expressed gene coding for a mitochondrial protein with a potential role in cristae morphology maintenance and/or oxidative phosphorylation with mutations recently associated with ALS. We characterized two distinct alleles: a deletion of 260 bp (gk3124) and a point mutation (ad2155). Both har-1 (gk3124) and har-1 (ad2155) worms display age-dependent motility defects leading to paralysis, degeneration of GABAergic neurons and altered mitochondrial health. The small molecules, pioglitazone and 2,4-thiazolidinedione, with known neuroprotective activity, and also shown to regulate mitochondrial health, suppressed several har-1 phenotypes. Moreover, dietary supplementation of L. rhamnosus HA-114 improved several ALS-related phenotypes in these har-1 mutants.  These findings may confirm a link between microbiota and ALS and can lead to future therapies, through the modulation of the intestinal environment. L. rhamnosus HA-114 is suitable for human consumption opening the possibility of modifying disease progression by dietary intervention. Furthermore, uncovering the complete neuroprotection pathway may give us insights into new genes and bioactive molecules able to modulate neurodegeneration, thus opening the door to new therapeutic approaches.

Keyphrases: C. elegans, Acides gras, Mitochondries, Neurodegeneration, Probiotics, Beta-oxidation, Amyotrophic lateral sclerosis, Neurons, Lipids, Fatty acids, Mitochondria