title: Marked inhibition of Na+, K(+)- ATPase activity and the respiratory chain by phytanic acid in cerebellum from young rats: possible underlying mechanisms of cerebellar ataxia in Refsum disease.
abstract: Refsum disease is an autosomal recessive disorder of peroxisomal metabolism biochemically characterized by highly elevated concentrations of phytanic acid (Phyt) in a variety of tissues including the cerebellum. Reduction of plasma Phyt levels by dietary restriction intake ameliorates ataxia, a common clinical manifestation of this disorder, suggesting a neurotoxic role for this branched-chain fatty acid. Therefore, considering that the underlying mechanisms of cerebellum damage in Refsum disease are poorly known, in the present study we tested the effects of Phyt on important parameters of bioenergetics, such as the activities of the respiratory chain complexes I to IV, creatine kinase and Na(+), K(+)- ATPase in cerebellum preparations from young rats. The activities of complexes I, II, I-III and II-III and Na(+), K(+)- ATPase were markedly inhibited (65-85%) in a dose-dependent manner by Phyt. In contrast, creatine kinase and complex IV activities were not altered by this fatty acid. Therefore, it is presumed that impairment of the electron flow through the respiratory chain and inhibition of Na(+), K(+)- ATPase that is crucial for synaptic function may be involved in the pathophysiology of the cerebellar abnormalities manifested as ataxia in Refsum disease and in other peroxisomal disorders in which brain Phyt accumulates.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600 - Anexo, CEP 90035-003 Porto Alegre, RS, Brazil.
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Ângela
authors.initials: Â
authors.lastname: Zanatta
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Carolina Maso
authors.initials: CM
authors.lastname: Viegas
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.forename: César Augusto João
authors.initials: CA
authors.lastname: Ribeiro
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004579:Electron Transport / Q000187:drug effects; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010831:Phytanic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012035:Refsum Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013569:Synapses / Q000201:enzymology* / Q000473:pathology
chemical_list: D045222:Electron Transport Chain Complex Proteins; D009419:Nerve Tissue Proteins; D010831:Phytanic Acid; D000254:Sodium-Potassium-Exchanging ATPase