Investigating the systemic pathological mechanisms of FUS and TDP-43
Keywords: diet modulation
neurodegenerative disorders
genetics
frontotemporal dementia (FTD)
amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders (NDDs), with no cures. These conditions sit on a spectrum and have overlapping clinical symptoms, genetics and pathology. In particular, FUS and TDP-43 inclusions have been observed in familial and sporadic cases of both conditions. FUS and TDP-43 are highly conserved and involved in several cellular processes, mainly RNA metabolism. These proteins are expressed in most tissues, however, their pathological effects have been mainly studied in neuronal tissues. ALS and FTD are considered multi-system disorders therefore peripheral alterations could be contributing to disease aetiology. For example, metabolic alterations have been shown to have disease-modifying effects in both conditions. This project investigated the systemic pathological mechanisms of FUS and TDP-43 using physiological knock-in mouse models carrying disease-relevant mutations. Unlike transgenic models, physiological models express the target endogenous levels, at the right place and time, ensuring that only mutation-specific effects are investigated. The TardbpM323K mouse and the partially humanised FusΔ14 mouse underwent an extensive phenotyping pipeline which revealed cognitive, motor and metabolic phenotypes in homozygous mice. Systemic transcriptomic analysis of the FusΔ14 homozygous mouse revealed tissue-specific mutation effects. In response to systemic glucose alterations, metabolic reprogramming occurred in the muscles and this preceded neuromuscular changes. Early brain morphological changes and innate behaviour deficits in these mice point to the developmental effects of the FusΔ14 mutation. Previous characterisation of the TardbpM323K mutation revealed late neuromuscular changes and motor phenotypes in homozygous mice. This project identified additional cognitive deficits, coupled with early brain structural changes. Metabolic phenotypes included increased body weights, increased fat mass and hypermetabolism. These phenotypes reintroduce the TardbpM323K homozygous mouse as a novel ALS-FTD model. Both mutations on the C57BL/6J background caused embryonic lethality in homozygosity. This lethality was rescued on a F1 hybrid genetic background (C57BL/6J x DBA/2J). The FusΔ14 mutation in heterozygosity produced different body composition effects between mouse strains. This demonstrates that genetic backgrounds can interact with mutation effects. Metabolic alterations have been documented across the ALS-FTD spectrum. Observational studies have shown that metabolic disturbances have contrasting effects on motor and cognitive functioning, suggesting that metabolic status can modify phenotypes within the spectrum. This hypothesis was investigated by modifying metabolic parameters using different diets in the TardbpM323K homozygous mouse. A high fat diet (HFD) and a matching control low fat diet (LFD) were used. The LFD modified metabolic parameters in homozygous mice to modulate mutation-driven motor phenotypes, in a sex-dependent manner. This data opens the door for patients to potentially modify their disease progression and phenotypes using diet as a therapeutic tool.