Abstract
In addition to key roles in embryonic neurogenesis and myelinogenesis, γ-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. In yeast, we have identified a new role for GABA that augments activity of the pivotal kinase, Tor1. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch9, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor1 inhibitor, rapamycin. To confirm these processes in mammals, we examined 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. These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA.
Highlights
In addition to key roles in embryonic neurogenesis and myelinogenesis, c-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter
We found that the UGA2, but not the UGA1 mutant of the GABA shunt pathway, partially inhibited pexophagy compared to the WT, as shown by the delay in degradation of the peroxisomal matrix protein, Pot1, at the 12-h time point (Supplementary Fig S2)
As rapamycin reduced reactive oxygen species (ROS) levels more than glutathione, and is known to induce pexophagy and mitophagy, we suggest that rapamycin overcomes the underlying cause of the disorder by reducing elevated mTOR activity to induce autophagy, clearing away old and damaged peroxisomes and mitochondria causing the high levels of ROS
Summary
In addition to key roles in embryonic neurogenesis and myelinogenesis, c-aminobutyric acid (GABA) serves as the primary inhibitory mammalian neurotransmitter. GABA inhibits the selective autophagy pathways, mitophagy and pexophagy, through Sch, the homolog of the mammalian kinase, S6K1, leading to oxidative stress, all of which can be mitigated by the Tor inhibitor, rapamycin. To confirm these processes in mammals, we examined the succinic semialdehyde dehydrogenase (SSADH)-deficient mouse model that accumulates supraphysiological GABA in the central nervous system and other tissues. Administration of rapamycin to these mice reduced mTOR activity, reduced the elevated mitochondrial numbers, and normalized aberrant antioxidant levels These results confirm a novel role for GABA in cell signaling and highlight potential pathomechanisms and treatments in various human pathologies, including SSADH deficiency, as well as other diseases characterized by elevated levels of GABA
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