title: Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
abstract: Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.
authors.affiliation: Jake Gittlen Cancer Research Foundation, Department of Pathology, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA. wjz105@psu.edu
authors.forename: William J
authors.initials: WJ
authors.lastname: Zinnanti
authors.forename: Jelena
authors.initials: J
authors.lastname: Lazovic
authors.forename: Cathy
authors.initials: C
authors.lastname: Housman
authors.forename: Kathryn
authors.initials: K
authors.lastname: LaNoue
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: Ian
authors.initials: I
authors.lastname: Simpson
authors.forename: Michael
authors.initials: M
authors.lastname: Woontner
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Goodman
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
authors.forename: Russell E
authors.initials: RE
authors.lastname: Jacobs
authors.forename: Keith C
authors.initials: KC
authors.lastname: Cheng
mesh_terms: D000375:Aging / Q000502:physiology*; D000592:Amino Acid Metabolism, Inborn Errors / Q000178:diet therapy / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000178:diet therapy / Q000473:pathology / Q000503:physiopathology; D002648:Child; D004032:Diet; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000378:metabolism / Q000627:therapeutic use; D018698:Glutamic Acid / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism*; D050770:Glutaryl-CoA Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D006709:Homoarginine / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008239:Lysine / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019906:Nuclear Magnetic Resonance, Biomolecular; D014364:Tryptophan / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005977:Glutarates; D006709:Homoarginine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D014364:Tryptophan; D050770:Glutaryl-CoA Dehydrogenase; C035736:glutaric acid; D005947:Glucose; D008239:Lysine