【摘 要】
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In mammals, including humans, several diseases associated with elevated levels of γ-amino-butyric acid (GABA), the primary inhibitory neurotransmitter, have be
【机 构】
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DivisionofBiologicalSciences,SectionofMolecularBiology,UniversityofCaliforniaSanDiego,LaJolla,CA,USA
【出 处】
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The 7th International Symposium on Autophagy 2015(第七届自噬国际研讨会
论文部分内容阅读
In mammals, including humans, several diseases associated with elevated levels of γ-amino-butyric acid (GABA), the primary inhibitory neurotransmitter, have been described, but their underlying causes are unknown.We have studied the effects of GABA on autophagy pathways in yeast and mice and have reported that GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase,S6K1, leading to oxidative stress (Lakhani et al., 2014).GABA also enhances the activity of the Tor1 kinase and the effects of GABA can be mitigated by the Tor1 inhibitor, rapamycin.We extended these studies to the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues.Mutant mice displayed increased mitochondrial numbers in the brain and liver,expected with a defect in mitophagy, and morphologically abnormal mitochondria.Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels.We will describe ongoing studies on the effects of other GABA metabolites on autophagy pathways, as well as our continuing mechanistic studies with yeast and mammalian model systems.
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