DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting

Yuskaitis, Christopher J.; Modasia, Jinita B.; Schrötter, Sandra; Rossitto, Leigh-Ana; Groff, Karenna J.; Morici, Christopher; Mithal, Divakar S.; Chakrabarty, Ram Prosad; Chandel, Navdeep S.; Manning, Brendan D.; Şahin, Mustafa

doi:10.1016/j.celrep.2022.111278

Cited by 12 publications

(11 citation statements)

References 83 publications

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“…Abundance or deficiency of AAs is always detected with various sensors via the mechanistic target of the rapamycin complex 1 (mTORC1), general control nonderepressible 2 (GCN2), or fibroblast growth factor 21 (FGF21) signaling pathway [ 9 ]. For instance, some AAs, such as leucine and arginine, are directly sensed [ 10 ], whereas others, such as methionine, are sensed in the form of their metabolites [ 11 ]. Therefore, a strict low-protein diet of only AAs may induce several nutritional risks that result in functional AA deficiency, rather than benefits for renal protection in DKD patients [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

Luo-kun

Zhang

et al. 2022

Nutrients

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Diabetic kidney disease (DKD) occurs in 25–40% of patients with diabetes. Individuals with DKD are at a significant risk of progression to end-stage kidney disease morbidity and mortality. At present, although renal function-decline can be retarded by intensive glucose lowering and strict blood pressure control, these current treatments have shown no beneficial impact on preventing progression to kidney failure. Recently, in addition to control of blood sugar and pressure, a dietary approach has been recommended for management of DKD. Amino acids (AAs) are both biomarkers and causal factors of DKD progression. AA homeostasis contributes to renal hemodynamic response and glomerular hyperfiltration alteration in diabetic patients. This review discusses the links between progressive kidney dysfunction and the metabolic homeostasis of histidine, tryptophan, methionine, glutamine, tyrosine, and branched-chain AAs. In addition, we emphasize the regulation effects of special metabolites on DKD progression, with a focus on causality and potential mechanisms. This paper may offer an optimized protein diet strategy with concomitant management of AA homeostasis to reduce the risks of DKD in a setting of hyperglycemia.

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Section: Introductionmentioning

confidence: 99%

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

Luo-kun

Zhang

et al. 2022

Nutrients

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“…IGF-1 and mTOR are downregulated by fasting, and their inhibition increases autophagy, reduces the accumulation of oxidative damage, and improves insulin sensitivity; all of which are thought to play major roles in the prevention of aging-related diseases [ 21 ]. Multiple studies in the disease models we reviewed found changes associated with IGF-1, mTOR, or the related AMPK pathway in AD [ 82 , 84 ], PD [ 96 ], MS [ 55 ] and epilepsy [ 118 , 119 , 120 ]. BDNF is a neurotropic factor known to increase neuronal regeneration that has been previously shown to mediate adult neurogenesis by DR in healthy adult mice [ 52 ] and BDNF is upregulated after dietary interventions in the brains of animal models of AD [ 82 ], PD [ 104 , 106 ], and MS [ 137 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hartman et al attempted to distinguish effects of CR from KD by testing ADF and ad libitum KD in multiple acute seizure tests in 3–4-week-old NIH Swiss mice, finding that ADF is detrimental in the 6 Hz and maximal electroshock (MES) seizure models, but protective against kainic acid induced seizures [ 116 ]. While Hartman et al did not find that ADF elevated the seizure threshold of mice injected with pentylenetetrazol (PTZ), Eagles and colleagues reported that 35% CR does elevate the PTZ seizure threshold in 5-week-old Sprague-Dawley rats [ 117 ], and another group showed that a 24-h fast reduced the proportion of 6–9-week-old mice developing seizures after a single PTZ dose [ 118 ]. Restricting 8-week-old Wistar rats to daily 2-h TRF reduces the proportion of seizures and deaths following pilocarpine injection [ 119 ].…”

Section: The Effect Of Dietary Interventions On Neurological Diseasesmentioning

confidence: 99%

“…Yuskaitis et al showed that the preventative effect of 24-h fasting on PTZ induced seizures was DEPDC5 dependent, as the seizure incidence of Depdc5cc+ mice was unchanged by fasting. In vitro experiments with neuronal cell cultures evaluating the effects of all amino acids showed that specifically leucine, arginine, and glutamine upregulated mTOR in a DEPDC5 dependent manner, suggesting that an important part of the anticonvulsive effect of 24-h fasting in the brain came from the change in amino acid balance [ 118 ].…”

Section: The Effect Of Dietary Interventions On Neurological Diseasesmentioning

confidence: 99%

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The Effects of Dietary Interventions on Brain Aging and Neurological Diseases

2022

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Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases.

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“… 98 Preclinical studies suggest a role for modulation of the mTOR pathway by the ketogenic diet, providing the basis for clinical studies ( Table 2 ). 70 , 99 , 100 Recent studies aimed at determining the efficacy of the ketogenic diet specifically in TSC and mTORopathies have shown that it results in seizure reduction, often within the first few months of initiation of the diet, but it does not guarantee long-term efficacy. 101 , 102 However, due to its known efficacy in drug-resistant epilepsy and tolerability in children, both the European consensus TSC guidelines and the International Ketogenic Diet Study Group recommend early consideration of the ketogenic diet in infants and young children with TSC when surgery is not an option.…”

Section: Medical Therapiesmentioning

confidence: 99%

Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions

Singh

Hadjinicolaou

Peters

et al. 2023

NDT

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Tuberous sclerosis complex (TSC) is a neurogenetic disorder that affects multiple organ systems, including the heart, kidneys, eyes, skin, and central nervous system. The neurologic manifestations have the highest morbidity and mortality, in particular in children. Clinically, patients with TSC often present with new-onset seizures within the first year of life. TSC-associated epilepsy is often difficult to treat and refractory to multiple antiseizure medications. Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder. An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes. Therefore, it is important to treat TSC-associated epilepsy aggressively, whether it be with pharmacological therapy, surgical intervention, and/or neuromodulation. This review discusses current and future pharmacological treatments for TSC-associated epilepsy, as well as the importance of early surgical evaluation for refractory epilepsy in children with TSC and consideration of neuromodulatory interventions in young adults.

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DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting

Cited by 12 publications

References 83 publications

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

The Effects of Dietary Interventions on Brain Aging and Neurological Diseases

Treatment-Resistant Epilepsy and Tuberous Sclerosis Complex: Treatment, Maintenance, and Future Directions

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