title: A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice.
abstract: Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice. Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43(A315T) mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS.
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Coughlan
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Luise
authors.initials: L
authors.lastname: Halang
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Ina
authors.initials: I
authors.lastname: Woods
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland prehn@rcsi.ie.
authors.forename: Jochen H M
authors.identifier: 0000-0003-3479-7794
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004734:Energy Metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008136:Longevity; D008159:Lumbar Vertebrae / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D000263:Adenylate Kinase; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C578077:Tardbp protein, mouse
keywords: AMPK; Amyotrophic lateral sclerosis; High-fat jelly diet; Motor neuron degeneration; Spinal cord; Standard pellet diet; TDP-43