Molecular and cellular determinants of LDL-receptor related protein (LRP) trafficking and sorting in hippocampal neurons

DONOSO M., BISBAL M, RETAMAL C, VAN KERKHOF P., BU G., MALHOTRA V., CACERES A., MARZOLO MP

Conferencia; 2nd ISN Special Neurochemistry Conference; 2006

International Society for Neurochemistry (ISN)

Neurons are highly polarized cells which extend several short,thick tapering dendrites and one functional distinct long thinaxon. The mechanisms that govern the polarized distributionof membrane proteins in neurons are still under intense study.LRP  is  a  highly  endocytic  and  recycling  receptor  from  theLDLR family that provides a convenient model for assessingcertain incompletely understood aspects of the protein sortingmechanisms  in  cells  with  polarized  phenotype,  includingneurons  where  the  receptor  in  expressed  in  the  somato-dendritic domain. We defined and functionally dissect sortingmotifs conformed by two tyrosine residues that we previouslyfound involved in LRP basolateral distribution in epithelialcells.  Strikingly,  we  distinguished  different  sorting  functionswithin a non-endocytic proximal N 26 PXY 29 motif. While Y 29determines  somato-dendritic  distribution  of  LRP,  the  N 26residue mediates exit from a sorting endosomes by recruitingsorting  nexin  17.  The  endocytic  motifs  YATL  and  a  distaldileucine, are also soma-to dendritic sorting signals, that whenmutated determine a non-polarized distribution of the recep-tor. The polarized distribution of LRP was also dependent onthe  expression/activity  of  protein  kinase  D1,  which  waspreviously  described  as  a  regulator  of  the  formation  ofbasolateral  carriers  from  trans-Golgi  Network  in  epithelialcells.   Our   results   demonstrate   that   the   somato-dendriticdistribution of LRP entails a multi-step process mediated bydifferent  sorting  motifs  at  the  biosynthetic  and  recyclingpathways, and provide new mechanistic insights on polarizedprotein sorting in neurons.