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-43A315T mice. Similar to our recent results in SOD1G93A mice, TDP-43A315T 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-43A315T 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-43A315T 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.

Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

“…Additionally, motor behavior was scored as previously described (34, 39) and Nlk reduction ameliorated gait impairment, tremor, hindlimb clasping, and kyphosis between P14-P22 (Figure 5J-N, Supplemental Figure 8, and Supplemental Video 1). Finally, because altering diet may affect the course of disease in transgenic ALS mouse models (40), we raised an independent cohort of Thy1-TDP Tg/Tg animals on a high fat/gel food diet and observed a similar improvement in motor behavior with a greater extension of survival with P1 Nlk ASO injections (Supplemental Figure 9).…”

TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis

“…This phenotypic artifact masked neurodegeneration in these mice, however a posterior study showed that when feeding the animals a high fat gel based diet extended their lifespan showing progressive ALS phenotype. 123 Subsequent mouse models were developed with more restricted promoters to isolate TDP-43 effects in the brain; however the results have also been highly heterogeneous. 36,122,124 Very recently a new TDP- 43 Altogether, further research is still needed to generate improved animal models in order to understand TDP-43 implication in disease and be used as tools to discover new drugs.…”

Existing and Emerging Metabolomic Tools for ALS Research

“…To date, no efficient treatment for ALS is available and studies leading to potential new treatment strategies remain of great importance [199,200]. Efforts have been made to find new therapeutics based on the suggested metabolic defects [8,98,[201][202][203][204][205], but partly due to the lack of knowledge about the metabolic defects in ALS, this search has not yet been successful. Therefore, we believe that the tools discussed in this review could play an important role in the search for new treatment strategies in ALS.…”