Effects of acute and chronic administration of methylmalonic and propionic acids on the in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of young rats

Abstract

We studied the e}ects of acute and chronic administration of methylmalonic (MMA) and propionic (PA) acids on the in vitro incorporation of 32 P into neurofilament subunits (NF-M and NF-L), α and β tubulins, from cerebral cortex of rats. In the chronic treatment, drugs were administered subcutaneously from day 6—17 post-partum (MMA 0.76-0.89 μmol\\g body weight and PA 0.93 μmo\\g body weight). In the acute treatment MMA and PA were injected "MMA 1.78 μmo\\g body weight and PA 1.90 μmol\\g body weight). Control animals received saline in the same volumes. The Triton-insoluble cytoskeletal fraction of control in treated animals was isolated and incubated with 32 P-ATP. Our results demonstrate that both drugs were able to inhibit 32 P in vitro incorporation into neurofilaments and tubulins. The acute administration of MMA decreased the in vitro 32 P incorporation into NF-L and a-tubulin subunit, whereas PA administration decreased the 32 P in vitro incorporation into NF-M, NF-L, and tubulins. On the other hand, chronic MMA administration induced a decreased 32 P in vitro incorporation into NF-M, while chronic treatment with propionate decreased the in vitro phosphorylation of NF-M and a-tubulin. This study provides consistent evidence that a decreased phosphorylation of cytoskeletal proteins is induced by MMA and PA metabolites which accumulate in methylmalonic and propionic acidemias respectively. Therefore, it is possible that an altered brain cytoskeletal metabolism could be related with the structural alterations of CNS observed in these disorders.