SPECIFIC ALTERATIONS IN LEVELS OF MANNOSE 6-PHOSPHORYLATED GLYCOPROTEINS IN DIFFERENT NEURONAL CEROID-LIPOFUSCINOSES

Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is g enerated on newly synthesized lysosomal proteins. This modification is specifically recognized by two Man-6-P receptors that direct the vesi cular transport of the lysosomal enzymes from the Golgi to a prelysoso mal compartment. The Man-6-P is rapidly removed in the lysosome of mos t cell types; however, in neurons the Man-6-P modification persists, I n this study we have examined the spectrum of Man-6-P-containing glyco proteins in brain specimens from patients with different neuronal cero id lipofuscinoses (NCLs). which are progressive neurodegenerative diso rders with established links to defects in lysosomal catabolism. We fi nd characteristic alterations in the Man-6-P glycoproteins in specimen s from late-infantile (LINCL), juvenile (JNCL) and adult (ANCL) patien ts, Man-6-P glycoproteins in LINCL patients were similar to controls, with the exception that the band corresponding to CLN2 a recent identi fied lysosomal enzyme whose deficiency results in this disease, was ab sent, In an ANCL patient, two Man-6-P glycoproteins were elevated in c omparison with normal controls, suggesting that this disease also resu lts from a perturbation in lysosomal hydrolysis. In JNCL, total levels of Man-6-P glycoproteins were 7-fold those of controls. In general th is was reflected by increased lysosomal enzyme activities in JNCL but three Man-6-P glycoproteins were elevated to an even greater degree. T hese are CLN2 and the unidentified proteins that are also highly eleva ted in the ANCL.