Subcellular localization of mannose 6-phosphate glycoproteins in rat brain

The intracellular transport of soluble lysosomal enzymes relies on the post -translational modification of N-linked oligosaccharides to generate mannos e 6-phosphate (Man 6-P) residues. In most cell types the Man 6-P signal is rapidly removed after targeting of the precursor proteins from the Golgi to lysosomes via interactions with Man 6-phosphate receptors, However, in bra in, the steady state proportion of lysosomal enzymes containing Man 6-P is considerably higher than in other tissues. As a first step toward understan ding the mechanism and biological significance of this observation, we anal yzed the subcellular localization of the rat brain Man 6-P glycoproteins by combining biochemical and morphological approaches, The brain Man 6-P glyc oproteins are predominantly localized in neuronal lysosomes with no evidenc e for a steady state localization in nonlysosomal or prelysosomal compartme nts. This contrasts with the clear endosome-like localization of the low st eady state proportion of mannose-6-phosphorylated lysosomal enzymes. in liv er. It therefore seems Likely that the observed high percentage of phosphor ylated species in brain is a consequence of the accumulation of lysosomal e nzymes in a neuronal lysosome that does not fully dephosphorylate the Man 6 -P moieties.