title: Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1.
abstract: Enzyme activities of a alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) and one of its constituent subunits, dihydrolipoamide dehydrogenase (E3), are reported to be reduced in non-CNS tissues of some patients with Friedreich's ataxia (FA); however, the results are highly conflicting. To determine whether an enzyme abnormality occurs in brain, we measured immunoreactive levels of the three alpha KGDHC subunits, namely, alpha-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and E3 in postmortem frontal, occipital and cerebellar cortices of 18 control subjects, 9 patients with FA and, for comparison, 12 patients with spinocerebellar ataxia type 1 (SCA1). Decreased (-20 to -31%) levels of E3 were observed in all three examined areas of the patients with FA with the changes statistically significant in cerebellar and frontal cortices. The E3 reduction could be explained by a loss of alpha KGDHC or other dehydrogenase complexes (e.g. pyruvate dehydrogenase complex) which utilize this subunit. In SCA1, enzyme changes were limited to E2 in cerebellar (-26%) and frontal (-19%) cortices. Although the E3 and E2 reductions are only slight, and may represent secondary events, the changes in this key Krebs cycle enzyme could exacerbate degenerative processes in both of the spinocerebellar ataxia disorders.
authors.affiliation: Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Mastrogiacomo
authors.forename: J
authors.initials: J
authors.lastname: LaMarche
authors.forename: S
authors.initials: S
authors.lastname: Dozić
authors.forename: G
authors.initials: G
authors.lastname: Lindsay
authors.forename: L
authors.initials: L
authors.lastname: Bettendorff
authors.forename: Y
authors.initials: Y
authors.lastname: Robitaille
authors.forename: L
authors.initials: L
authors.lastname: Schut
authors.forename: S J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000217:Acyltransferases / Q000032:analysis; D000328:Adult; D000704:Analysis of Variance; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D002525:Cerebellar Cortex / Q000201:enzymology; D005621:Friedreich Ataxia / Q000201:enzymology*; D005625:Frontal Lobe / Q000201:enzymology; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000032:analysis* / Q000378:metabolism; D046911:Macromolecular Substances; D009778:Occipital Lobe / Q000201:enzymology; D011180:Postmortem Changes; D012016:Reference Values; D013132:Spinocerebellar Degenerations / Q000201:enzymology*; D013997:Time Factors
chemical_list: D046911:Macromolecular Substances; D007655:Ketoglutarate Dehydrogenase Complex; D000217:Acyltransferases; C021515:dihydrolipoamide succinyltransferase