title: Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition.
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.
authors.affiliation: Division of Biological Sciences, Section of Molecular Biology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Ronak
authors.initials: R
authors.lastname: Lakhani
authors.forename: Kara R
authors.initials: KR
authors.lastname: Vogel
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Burnett
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
authors.forename: Suresh
authors.initials: S
authors.lastname: Subramani
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D002658:Developmental Disabilities; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase; D058570:TOR Serine-Threonine Kinases