EFFECTS OF ACUTE AND CHRONIC ADMINISTRATION OF METHYLMALONIC AND PROPIONIC ACIDS ON THE IN-VITRO INCORPORATION OF P-32 INTO CYTOSKELETAL PROTEINS FROM CEREBRAL-CORTEX OF YOUNG-RATS

We studied the effects of acute and chronic administration of methylma lonic (MMA) and propionic (PA) acids on the in vitro incorporation of P-32 into neurofilament subunits (NF-M and NF-L), alpha and beta tubul ins, from cerebral cortex of rats. In the chronic treatment, drugs wer e administered subcutaneously from day 6-17 post-partum (MMA 0.76-0.89 mu mol/g body weight and PA 0.93 mu mol/g body weight). In the acute treatment MMA and PA were injected (MMA 3.78 mu mol/g body weight and PA 3.90 mu mol/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 P-32-ATP. Our results demonstrate that both drugs were able to inhibit 32P in vitro incorpo ration into neurofilaments and tubulins. The acute administration of M MA decreased the in vitro 32P incorporation into NF-L and a-tubulin su bunit, whereas PA administration decreased the 32P in vitro incorporat ion into NF-M, NF-L, and tubulins. On the other hand, chronic MMA admi nistration induced a decreased 32P in vitro incorporation into NF-M, w hile chronic treatment with propionate decreased the in vitro phosphor ylation 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 propio nic acidemias respectively. Therefore, it is possible that an altered brain cytoskeletal metabolism could be related with the structural alt erations of CNS observed in these disorders. (C) 1998 Elsevier Science Ltd. All rights reserved.