公募シンポジウム

公募シンポジウム14【脳機能や老化・疾患を制御する多様な代謝システム】

2021/10/1　16:00～18:00　ZOOM B会場 S14-1 老化と神経変性疾患における脳神経細胞のグルコース代謝の役割 Neuronal glucose metabolism in brain aging and age-related neurodegenerative diseases ^○安藤香奈絵東京都立大学大学院理学研究科 ^○Kanae Ando Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan Aging is associated with progressive declines in brain integrity and functions alongside increases in vulnerability and the risk of developing neurological diseases. Energy metabolism plays a central role in organismal aging, but there is conflicting evidence about the roles of neuronal glucose metabolism in aging and lifespan. The brain requires a large amount of energy, and aging is associated with declines in both glucose availability and energy production in the brain. This implies that strategies aimed at increasing glucose metabolism in neurons may protect against organismal aging. By contrast, dietary restriction (DR), which causes circulating glucose concentrations to fall, have been demonstrated to have anti-aging effects. Thus, the pro-aging effects of reductions in brain glucose metabolism and the anti-aging effects of reducing circulating glucose are apparently contradictory. To solve this discrepancy, we analyzed metabolic changes in the brain neurons of Drosophila during aging. We found decreased ATP concentration in the neurons of aged flies, which was correlated with decreased glucose content, expression of glucose transporter and glycolytic enzymes and mitochondrial quality. Increasing glucose uptake maintained ATP levels, suppressed age-dependent locomotor deficits and extended the life span. Increasing neuronal glucose uptake during dietary restriction resulted in the longest lifespans, suggesting an additive effect of enhancing glucose availability during a bioenergetic challenge on aging. Furthermore, enhancement of glucose uptake in neurons protects against neurodegeneration in tauopathy model. These results suggest that reduction in neuronal glucose metabolism underlies aging and neuronal vulnerability under disease condition.		2021/10/1　16:00～18:00　ZOOM B会場 S14-2 脳内グルタミン酸代謝の制御機構と疾患発症との関わり Regulatory mechanism of glutamate metabolism in CNS health and disease ^○照沼美穂新潟大学大学院医歯学総合研究科口腔生化学分野 ^○Miho Terunuma Niigata University Graduate School of Medical and Dental Sciences, Division of Oral Biochemistry Metabolism of glutamate, the major excitatory neurotransmitter and precursor of γ-aminobutyric acid (GABA), is mainly dependent on glutamine synthetase (GS) in astrocytes. GS is the only enzyme known to date that is capable of converting glutamate and ammonia to glutamine in the mammalian brain. Excess glutamate is an epileptogenic and neurotoxic agent and reduced expression and activity of GS has been found in the patient with mesial temporal lobe epilepsy. Hyperammonemia is also frequently seen in unprovoked convulsive seizure patients (Sato et al, Seizure, 2016). Therefore, fine-tuning glutamate and ammonia metabolism through GS is important for maintaining brain health. In this symposium, I will introduce the previously unknown molecular mechanism of GS down-regulation in hyperammonemic and hyperglutamate condition which could be the novel target for the development of anti-epileptic drugs.

2021/10/1　16:00～18:00　ZOOM B会場 S14-3 アストロサイトからの乳酸輸送によるシナプス伝達と細胞興奮性のオンサイト維持 On-site supply of lactate supports synaptic transmission and membrane excitability ^○加藤総夫、永瀬将志東京慈恵会医科大学神経科学研究部 ^○Fusao Kato, Masashi Nagase Department of Neuroscience, Jikei University School of Medicine Astrocytic lactate supply through monocarboxylate transporters (MCTs) plays an essential role in supporting energy-consuming neuronal activities, such as excitatory transmission (Nagase et al., J Neurosci, 2014). However, it remains unclear whether such a role of MCTs is generally observed in other brain regions. We examined and compared the effects of pharmacological inhibition of MCTs on synaptic transmissions and membrane potentials in four distinct brain regions to address this issue. The membrane currents and potentials were recorded from Purkinje neurons in the cerebellum, pyramidal neurons in the hippocampus CA1, and neurons in the lateral and central amygdala in brain slices of mice and rats using whole-cell recordings. Alpha-cyano-4-hydroxycinnamic acid (4-CIN), an MCT inhibitor, significantly decreased the amplitude of EPSCs in all regions examined. By contrast, 4-CIN differentially affected paired-pulse ratio (PPR), an index of the presynaptic release probability, and membrane potential. 4-CIN significantly increased PPR in the cerebellum and hippocampus but not in the lateral and central amygdala. 4-CIN induced hyperpolarization in the cerebellum, hippocampus, and lateral amygdala in a manner dependent on the K_ATP channel, but depolarization in the central amygdala. These results suggest that an on-site supply of lactate is necessary for maintaining excitatory synaptic activities in various brain regions, whereas it plays distinct roles in regulating presynaptic release and membrane potential in different brain regions. These results suggest that astrocytic support of neuronal activities through providing energy sources is multifaceted with various modes and mechanisms, affecting brain functions in various pathological situations.		2021/10/1　16:00～18:00　ZOOM B会場 S14-4 代謝による個体老化の臨界期制御 On-site supply of lactate supports synaptic transmission and membrane excitability ^○三浦正幸東京大学大学院薬学系研究科遺伝学教室 ^○Masayuki Miura Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo While aging is thought to progress gradually, using the temporal and regional gene expression targeting (TARGET) system in Drosophila, expression of expanded-polyglutamine in compound eyes caused more severe neurodegeneration in middle-aged flies than in young flies. This observation suggested that the age-related change in physiological property could trigger late-onset diseases, including neurodegeneration. We hypothesized the existence of the critical period at which the rapid progression of aging turns on. Aging progression is largely affected by nutrition. Dietary restriction can be used as a standard regimen to extend lifespan from yeast to primates. Reductions in specific nutrients, such as amino acids, can also promote organismal lifespan extension. We combined Drosophila genetics and metabolome analysis for the aging study. We revealed that the S-adenosylmethionine (SAM), a metabolite synthesized from methionine, but not methionine itself, is a key regulatory metabolite for Drosophila lifespan regulation. We also found that the gene expression response on methionine restriction changed drastically around the critical period of aging. I will discuss molecular determinants of the critical period of aging that is responsible for methionine restriction.