Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under the control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of ALS; however, pre-mature sudden death due to intestinal obstruction halts disease phenotype progression in 100% C57Bl6/J congenic TDP-43(A315T) mice. We recently identified elevated adenosine-mono-phosphate kinase (AMPK) activation in SOD1(G93A) mice, indicating increased energetic stress during disease progression. Similar to SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased AMPK activation at postnatal day (PND) 80. We therefore investigated the effects of a high fat jelly diet on bioenergetic status and life span in TDP-43(A315T) mice. No difference in AMPK activation was detected in high fat jelly-fed TDP-43(A315T) mice up to PND 120. Direct comparison of high fat jelly diet and standard pellet diet mice also showed decreased phosphorylation of acetyl-CoA carboxylase (ACC) at early stage time points on high fat jelly diet. Exposure to high fat jelly diet prevented sudden death and extended survival (147±27 days compared to 102±19 days on standard pellet diet; p=<0.001). High fat jelly-fed mice developed a motor neuron disease phenotype with significantly decreased body weight from PND 80 onward that was characterised by deficits in Rotarod abilities (PND 130, 130, 150) and stride length measurements (PND 100 onward). Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining of motor neurons in the lumbar spinal cord. Our work suggests that a high fat jelly diet vastly improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress. Our data additionally indicate the potential benefit of a high fat jelly diet in TDP-43-associated ALS.
Royal College of Surgeons in Ireland ->