Amyotrophic lateral sclerosis is a devastating neurodegenerative disease that involves loss of motor neurons important for voluntary movement. Genetic factors enhance risk to develop ALS or the related disorder Frontotemporal dementia (FTD), but many people with a genetic risk factor never develop the disease. This suggests that environmental exposures are important modifiers of if and when someone will develop ALS/FTD. We found that mice that model a common ALS/FTD mutation develop inflammation in their brain and spinal cord that was highly dependent on signals derived from gut microbes(Burberry et al., 2020). Ongoing work in the lab aims to identify the microbes and microbial byproducts in the gut that contribute to neural inflammation in FTD/ALS patients, to identify the key physiologic pathways that promote neurodegeneration and to evaluate patients’ gut microbiome as a biomarker.
C9orf72 suppresses systemic and neural inflammation induced by gut bacteria
Aaron Burberry, Michael F. Wells, Francesco Limone, Alexander Couto, Kevin S. Smith, James Keaney, Gaëlle Gillet, Nick Gastel, Jin-Yuan Wang, Olli Pietilainen, and al.
A hexanucleotide-repeat expansion in C9ORF72 is the most common genetic variant that contributes to amyotrophic lateral sclerosis and frontotemporal dementia1,2. The C9ORF72 mutation acts through gain- and loss-of-function mechanisms to induce pathways that are implicated in neural degeneration3,4,5,6,7,8,9. The expansion is transcribed into a long repetitive RNA, which negatively sequesters RNA-binding proteins5 before its non-canonical translation into neural-toxic dipeptide proteins3,4. The failure of RNA polymerase to read through the mutation also reduces the abundance of the endogenous C9ORF72 gene product, which functions in endolysosomal pathways and suppresses systemic and neural inflammation6,7,8,9. Notably, the effects of the repeat expansion act with incomplete penetrance in families with a high prevalence of amyotrophic lateral sclerosis or frontotemporal dementia, indicating that either genetic or environmental factors modify the risk of disease for each individual. Identifying disease modifiers is of considerable translational interest, as it could suggest strategies to diminish the risk of developing amyotrophic lateral sclerosis or frontotemporal dementia, or to slow progression. Here we report that an environment with reduced abundance of immune-stimulating bacteria10,11 protects C9orf72-mutant mice from premature mortality and significantly ameliorates their underlying systemic inflammation and autoimmunity. Consistent with C9orf72 functioning to prevent microbiota from inducing a pathological inflammatory response, we found that reducing the microbial burden in mutant mice with broad spectrum antibiotics—as well as transplanting gut microflora from a protective environment—attenuated inflammatory phenotypes, even after their onset. Our studies provide further evidence that the microbial composition of our gut has an important role in brain health and can interact in surprising ways with well-known genetic risk factors for disorders of the nervous system.
@article{nature2020bacteria,author={Burberry, Aaron and Wells, Michael F. and Limone, Francesco and Couto, Alexander and Smith, Kevin S. and Keaney, James and Gillet, Gaëlle and van Gastel, Nick and Wang, Jin-Yuan and Pietilainen, Olli and et al.},title={C9orf72 suppresses systemic and neural inflammation induced by gut bacteria},journal={Nature},volume={582},number={7810},pages={89-94},year={2020},month=may,doi={10.1038/s41586-020-2288-7},}
