Up-regulation of cation-independent mannose 6-phosphate receptor and endosomal-lysosomal markers in surviving neurons after 192-IgG-saporin administrations into the adult rat brain.
The cation-independent mannose 6-phosphate receptor (CI-MPR) is a single transmembrane domain glycoprotein that plays a major role in the trafficking of lysosomal enzymes from the trans-Golgi network to the endosomal-lysosomal (EL) system. Because dysfunction of EL system is associated with a variety of neurodegenerative disorders, it is possible that the CI-MPR may have a role in regulating neuronal viability after toxicity/injury. In the present study, we report that 192-IgG-saporin-induced loss of basal forebrain cholinergic neurons causes a transient up-regulation of CI-MPR protein levels in surviving neurons of the basal forebrain and frontal cortex but not in the brainstem region, which was relatively spared by the immunotoxin. This was accompanied by a parallel time-dependent increase in other EL markers, ie, cathepsin D, Rab5, and LAMP2 in the basal forebrain region, whereas in the frontal cortex the levels of cathepsin D, and to some extent Rab5, were increased. Given the critical role of the EL system in the clearance of abnormal proteins in response to changing conditions, it is likely that the observed increase in the CI-MPR and components of the EL system in surviving neurons after 192-IgG-saporin treatment represents an adaptive mechanism to restore the metabolic/structural abnormalities induced by the loss of cholin-ergic neurons.
Hawkes
Cheryl
C
Centre for Alzheimer and Neurodegenerative Research, Departments of Medicine (Neurology) and Psychiatry, University of Alberta, Edmonton, Alberta, Canada T6G 2B7.
Kabogo
Doreen
D
Amritraj
Asha
A
Kar
Satyabrata
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002402:Cathepsin D / Q000032:analysis; D002470:Cell Survival; D011992:Endosomes / Q000201:enzymology*; D052119:Lysosomal-Associated Membrane Protein 2 / Q000032:analysis; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D015854:Up-Regulation; D020696:rab5 GTP-Binding Proteins / Q000032:analysis
C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D052119:Lysosomal-Associated Membrane Protein 2; D017527:Receptor, IGF Type 2; D011950:Receptors, Cholinergic; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D002402:Cathepsin D; D020696:rab5 GTP-Binding Proteins