Glutaric acid and its metabolites cause apoptosis in immature oligodendrocytes: a novel mechanism of white matter degeneration in glutaryl-CoA dehydrogenase deficiency

Pediatr Res. 2005 Jun;57(6):771-6. doi: 10.1203/01.PDR.0000157727.21503.8D. Epub 2005 Mar 17.


Glutaryl-CoA dehydrogenase deficiency is an inherited metabolic disease characterized by elevated concentrations of glutaric acid (GA) and its metabolites glutaconic acid (GC) and 3-hydroxy-glutaric acid (3-OH-GA). Its hallmarks are striatal and cortical degeneration, which have been linked to excitotoxic neuronal cell death. However, magnetic resonance imaging studies have also revealed widespread white matter disease. Correspondingly, we decided to investigate the effects of GA, GC, and 3-OH-GA on the rat immature oligodendroglia cell line, OLN-93. For comparison, we also exposed the neuroblastoma line SH-SY5Y and the microglia line BV-2 to GA, GC, and 3-OH-GA. Cell viability was measured by metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium. Flow cytometry was used to assess apoptosis via annexin-V, anti-active caspase-3 antibody, and propidium iodide staining. GA, GC, and 3-OH-GA reduced OLN-93 oligodendroglia cell viability in a dose-dependent manner. Toxicity of GA, GC, and 3-OH-GA was abrogated by preincubation with the pan-caspase inhibitor z-VAD-fmk. Apoptosis but not necrosis was detected at various stages (early: annexin-V; effector: caspase-3) after 24-48 h of incubation with GA, GC, or 3-OH-GA in OLN-93 but not in neuroblastoma or microglia cells. OLN-93 lacked expression of N-methyl-d-aspartate receptors, making classical glutamatergic excitotoxicity an unlikely explanation for the selective toxicity of GA, GC, and 3-OH-GA for OLN-93 cells. GA, GC, and 3-OH-GA directly initiate the apoptotic cascade in oligodendroglia cells. This mechanism may contribute to the white matter damage observed in glutaryl-CoA dehydrogenase deficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Base Sequence
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / metabolism
  • Brain Diseases, Metabolic, Inborn / pathology
  • Caspase Inhibitors
  • Cell Differentiation
  • Cell Line
  • Glutarates / metabolism
  • Glutarates / toxicity*
  • Glutaryl-CoA Dehydrogenase
  • Humans
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / metabolism
  • Oligodendroglia / drug effects*
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology*
  • Oxidoreductases Acting on CH-CH Group Donors / deficiency*
  • Oxidoreductases Acting on CH-CH Group Donors / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism


  • 3-hydroxyglutaric acid
  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Glutarates
  • RNA, Messenger
  • Receptors, Glutamate
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • glutaconic acid
  • Oxidoreductases Acting on CH-CH Group Donors
  • Glutaryl-CoA Dehydrogenase
  • glutaric acid