Newly synthesized enzymes destined for h sosomal localization contain mannose 6-phosphate (Man6-P... more Newly synthesized enzymes destined for h sosomal localization contain mannose 6-phosphate (Man6-P) residues, allowing interaction with MimA-l' receptors (Ml'Ksi and subsequent intracellular targeting to the lysosome. In most cultured cells, lysosomal enzymes are rapidly dephos- phorylated after targeting, but in some transformed cell lines, these proteins retain the Man6-P marker. To investigate the significance of this in human malignancy, we
Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative... more Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal prote- ase tripeptidyl peptidase 1 (TPP1). LINCL is characterized clinically by progressive motor and cognitive decline, and premature death. Enzyme-replacement therapy (ERT) is currently available for lysosomal storage diseases affecting peripheral tissues, but has not been used in patients
Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesiz... more Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesized lysosomal proteins. This modification is specifically recognized by two Man-6-P receptors that direct the vesicular transport of the lysosomal enzymes from the Golgi to a prelysosomal compartment. The Man-6-P is rapidly removed in the lysosome of most cell types; however, in neurons the Man-6-P modification persists. In this study we have examined the spectrum of Man-6-P-containing glycoproteins in brain specimens from patients with different neuronal ceroid lipofuscinoses (NCLs), which are progressive neurodegenerative disorders with established links to defects in lysosomal catabolism. We find characteristic alterations in the Man-6-P glycoproteins in specimens from late-infantile (LINCL), juvenile (JNCL) and adult (ANCL) patients. Man-6-P glycoproteins in LINCL patients were similar to controls, with the exception that the band corresponding to CLN2, a recently identified lysosomal...
Two proteins have been implicated in the mannose 6-phosphate-dependent transport of lysosomal enz... more Two proteins have been implicated in the mannose 6-phosphate-dependent transport of lysosomal enzymes to lysosomes: the 300kDa cation-independent and the 46kDa cation-dependent mannose 6-phosphate receptors (CI- and CD-MPRs). The mammalian CI-MPR also mediates endocytosis and clearance of insulin-like growth factor II (IGF-II). Mutant mice that lack the CD-MPR are viable, mice that lack the CI-MPR accumulate high levels of IGF-II and usually die perinatally, whereas mice that lack both IGF-II and CI-MPR are viable. To investigate the relative roles of the MPRs in the targeting of lysosomal enzymes in vivo, we analysed the effect of a deficiency of either MPR on lysosomal enzyme activities in animals lacking IGF-II. In CD-MPR-deficient mice, most activities were relatively normal in solid tissues and some were marginally elevated in serum. In CI-MPR-deficient mice, some enzyme activities were moderately decreased in solid tissues and multiple enzymes were markedly elevated in serum. ...
Newly synthesized enzymes destined for h sosomal localization contain mannose 6-phosphate (Man6-P... more Newly synthesized enzymes destined for h sosomal localization contain mannose 6-phosphate (Man6-P) residues, allowing interaction with MimA-l' receptors (Ml'Ksi and subsequent intracellular targeting to the lysosome. In most cultured cells, lysosomal enzymes are rapidly dephos- phorylated after targeting, but in some transformed cell lines, these proteins retain the Man6-P marker. To investigate the significance of this in human malignancy, we
Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative... more Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive neurodegenerative disease caused by mutations in CLN2, which encodes the lysosomal prote- ase tripeptidyl peptidase 1 (TPP1). LINCL is characterized clinically by progressive motor and cognitive decline, and premature death. Enzyme-replacement therapy (ERT) is currently available for lysosomal storage diseases affecting peripheral tissues, but has not been used in patients
Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesiz... more Mannose 6-phosphate (Man-6-P) is a carbohydrate modification that is generated on newly synthesized lysosomal proteins. This modification is specifically recognized by two Man-6-P receptors that direct the vesicular transport of the lysosomal enzymes from the Golgi to a prelysosomal compartment. The Man-6-P is rapidly removed in the lysosome of most cell types; however, in neurons the Man-6-P modification persists. In this study we have examined the spectrum of Man-6-P-containing glycoproteins in brain specimens from patients with different neuronal ceroid lipofuscinoses (NCLs), which are progressive neurodegenerative disorders with established links to defects in lysosomal catabolism. We find characteristic alterations in the Man-6-P glycoproteins in specimens from late-infantile (LINCL), juvenile (JNCL) and adult (ANCL) patients. Man-6-P glycoproteins in LINCL patients were similar to controls, with the exception that the band corresponding to CLN2, a recently identified lysosomal...
Two proteins have been implicated in the mannose 6-phosphate-dependent transport of lysosomal enz... more Two proteins have been implicated in the mannose 6-phosphate-dependent transport of lysosomal enzymes to lysosomes: the 300kDa cation-independent and the 46kDa cation-dependent mannose 6-phosphate receptors (CI- and CD-MPRs). The mammalian CI-MPR also mediates endocytosis and clearance of insulin-like growth factor II (IGF-II). Mutant mice that lack the CD-MPR are viable, mice that lack the CI-MPR accumulate high levels of IGF-II and usually die perinatally, whereas mice that lack both IGF-II and CI-MPR are viable. To investigate the relative roles of the MPRs in the targeting of lysosomal enzymes in vivo, we analysed the effect of a deficiency of either MPR on lysosomal enzyme activities in animals lacking IGF-II. In CD-MPR-deficient mice, most activities were relatively normal in solid tissues and some were marginally elevated in serum. In CI-MPR-deficient mice, some enzyme activities were moderately decreased in solid tissues and multiple enzymes were markedly elevated in serum. ...
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Papers by Peter Lobel