Session: 7

PS7-18 | Effects of phenylalanine incorporation into the C-terminus of alpha-tubulin on axonal transport

Agustina Zorgniotti

Centro de Investigaciones en Química Biológica (CIQUIBIC - CONICET) - Dpto. de Química Biológica Ranwel Caputto - Universidad Nacional de Córdoba

Phenylketonuria (PKU) is a metabolic disorder caused by a deficiency in the phenylalanine hydroxylase enzyme, resulting in the accumulation of phenylalanine (Phe). Elevated plasma levels of Phe cause microcephaly, epilepsy, permanent intellectual disability, delayed development, and motor disorders. These symptoms appear to be a consequence of neuronal cell loss, dendritic simplification and synaptic density reduction.
Tubulin, the protein constituent of microtubules, is subjected to removal and re-addition of the tyrosine (Tyr) residue encoded at the C-terminus of its α-chain, and there is increasing evidence of the role of this post-translational modification in various specialized microtubule functions. We have previously demonstrated both, in vitro and in vivo, that Phe can be cyclically incorporated and released from α-tubulin, with kinetics similar to those of Tyr . Now, we examined the effects of Phe treatment on different cellular parameters. We observed alterations in mitochondrial transport along the axon of hippocampal neurons and changes in the distribution of these organelles. In addition, we found abnormal interactions between Phe-enriched microtubules and molecular motors that participate in organelles transport. Our findings could be relevant for the brain dysfunctions observed in PKU patients since the proper intracellular distribution of mitochondria is crucial for neuronal development, synaptic transmission and plasticity.