TY  - JOUR
AU  - Rondelli, Valeria
AU  - Koutsioumpas, Alexandros
AU  - Di Cola, Emanuela
AU  - Fragneto, Giovanna
AU  - Grillo, I.
AU  - Del Favero, Elena
AU  - Colombo, Laura
AU  - Cantù, Laura
AU  - Brocca, Paola
AU  - Salmona, Mario
TI  - Dysmyelination and glycolipid interference caused by phenylalanine in phenylketonuria
JO  - International journal of biological macromolecules
VL  - 221
SN  - 0141-8130
CY  - New York, NY [u.a.]
PB  - Elsevier
M1  - FZJ-2022-06264
SP  - 784 - 795
PY  - 2022
AB  - Phenylketonuria (PKU) is a metabolic disorder connected to an excess of phenylalanine (Phe) in the blood and tissues, with neurological consequences. The disease's molecular bases seem to be related to the accumulation of Phe at the cell membrane surface. Radiological outcomes in the brain demonstrate decreased water diffusivity in white matter, involving axon dysmyelination of not yet understood origin. We used a biophysical approach and model membranes to extend our knowledge of Phe–membrane interaction by clarifying Phe's propensity to affect membrane structure and dynamics based on lipid composition, with emphasis on modulating cholesterol and glycolipid components to mimic raft domains and myelin sheath membranes. Phe showed affinity for the investigated membrane mimics, mainly affecting the Phe-facing membrane leaflet. The surfaces of our neuronal membrane raft mimics were strong anchoring sites for Phe, showing rigidifying effects. From a therapeutic perspective, we further investigated the role of doxycycline, known to disturb Phe packing, unveiling its action as a competitor in Phe interactions with the membrane, suggesting its potential for treatment in the early stages of PKU. Our results suggest how Phe accumulation in extracellular fluids can impede normal growth of myelin sheaths by interfering with membrane slipping and by remodulating free water and myelin-associated water contents.
LB  - PUB:(DE-HGF)16
C6  - 36099998
UR  - <Go to ISI:>//WOS:000860501900004
DO  - DOI:10.1016/j.ijbiomac.2022.09.062
UR  - https://juser.fz-juelich.de/record/916472
ER  -