Of Sex, Gut and Brain: Functional Studies in a Mouse Model of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a spectrum of neurodegenerative diseases characterized by the progressive loss of the motoneurons (typical of ALS), and cognitive dysfunction (characteristic of FTD). Studies have previously identified biological sex as an important determinant in the presentation and risk of ALS-FTD, but the mechanisms underlying sex differences in disease are poorly understood. Sexual dimorphism is also evident in a mutant human TAR DNA binding protein 43 (TDP43) mouse model of ALS-FTD, whereby males have a much shorter lifespan than females. Interestingly, these mice exhibit an abnormally enlarged gut, suggesting an involvement of the gut microbiota (i.e., the collective microorganisms such as bacteria, viruses, and fungi that populate the organ and regulate its physiology) in disease. Emerging studies suggest that gut microbiota is a key determinant of ALS disease. In humans, the microbiota composition varies significantly between males and females, suggesting that such variation may affect the male susceptibility to the disease. Using 16S sequencing, I found alterations in the gut microbiota of TDP43 mice: the abundance of beneficial bacteria species is reduced in the gut of the mice. The gut microbiota changes are sex- and age-dependent. Furthermore, there is a disparity in the disease onset and survival between the female non-breeder and female breeder mice that correlates with a higher abundance of pro-inflammatory bacteria in the gut of the latter. I then induced inflammation in female TDP43 non-breeders with a bacterial product derived from one of the bacterial species enriched in the short-lived female TDP43 breeder mice, namely lipopolysaccharides (LPS). I found that LPS treatment exacerbates motoneuron disease and shortens the lifespan of the mice in a manner reminiscent of the survival of female TDP43 breeders and male TPD43 mice. Taken together, my results suggest that neurodegeneration and survival of TDP43 mice are associated with gut microbiota dysbiosis in a sex-dependent manner. My findings also implicate gut inflammation in disease progression. My work provides novel and crucial insights into the role of gut microbiota in ALS-FTD with implications for future personalized therapeutic interventions in individuals suffering from these diseases.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Medicine – Neuroscience

Grantor

Cumming School of Medicine

Year dc:date.issued

2022

Author dc:creator

• Lee, Sukyoung

Advisors dc:contributor.advisor

• Pfeffer, Gerald
• Nguyen, Minh Dang

Committee members dc:contributor.committeemember

• Pittman, Quentin
• Sharkey, Keith

• ALS
• Gut microbiota
• FTD
• TDP43

Language dc:language.iso

English

DOI

https://dx.doi.org/10.11575/PRISM/dspace/41338

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/116494