Post-Translational Incorporation of L-Phenylalanine into the C-Terminus of alpha-Tubulin as a Possible Cause of Neuronal Dysfunction

DITAMO, Y; DENTESANO, YM; PURRO, SA; ARCE, CA; BISIG, CG

Scientific Reports

Nature Publishing Group

Año: 2016

α-Tubulin C-terminus undergoes post-translational, cyclic tyrosination/detyrosination, andL-Phenylalanine (Phe) can be incorporated in place of tyrosine. Using cultured mouse brain-derivedcells and an antibody specific to Phe-tubulin, we showed that: (i) Phe incorporation into tubulin isreversible; (ii) such incorporation is not due to de novo synthesis; (iii) the proportion of modifiedtubulin is significant; (iv) Phe incorporation reduces cell proliferation without affecting cell viability;(v) the rate of neurite retraction declines as level of C-terminal Phe incorporation increases; (vi) thisinhibitory effect of Phe on neurite retraction is blocked by the co-presence of tyrosine; (vii) microtubuledynamics is reduced when Phe-tubulin level in cells is high as a result of exogenous Phe addition andreturns to normal values when Phe is removed; moreover, microtubule dynamics is also reduced whenPhe-tubulin is expressed (plasmid transfection). It is known that Phe levels are greatly elevated inblood of phenylketonuria (PKU) patients. The molecular mechanism underlying the brain dysfunctioncharacteristic of PKU is unknown. Beyond the differences between human and mouse cells, it isconceivable the possibility that Phe incorporation into tubulin is the first event (or among the initialevents) in the molecular pathways leading to brain dysfunctions that characterize PKU.