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Keywords:

  • autophagy;
  • GABA;
  • mTOR;
  • rapamycin;
  • SSADH deficiency

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.

Synopsis

Thumbnail image of graphical abstract

Defects in GABA metabolism lead to its accumulation, which can cause severe neurological and behavioral disorders like SSADH deficiency. By activating mTOR/Tor, GABA inhibits selective autophagy pathways, suggesting a therapeutic application for mTOR inhibitors in GABA metabolic disorders.

  • Novel role for GABA in cell signaling
  • Elevated GABA increases mTOR activity
  • Inhibition of mitophagy and pexophagy caused by elevated GABA increases oxidative stress
  • Mice that accumulate GABA in tissues have increased mitochondria in the brain and liver
  • The mTOR inhibitor rapamycin can reduce mitochondria numbers in mice with elevated GABA and thereby reduce oxidative stress