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The Journal of Neuroscience, October 1, 1998, 18(19):7750-7756

Expression and Endocytosis of Lysosomal Aspartylglucosaminidase in Mouse Primary Neurons

Aija Kyttälä¹, Outi Heinonen¹, Leena Peltonen^{1, 2}, and Anu Jalanko¹

¹ Department of Human Molecular Genetics, National Public Health Institute, and ² Department of Medical Genetics, University of Helsinki, FIN-00300 Helsinki, Finland

Aspartylglucosaminuria (AGU) is a neurodegenerative lysosomal storage disease that is caused by mutations in the gene encoding for a soluble hydrolase, aspartylglucosaminidase (AGA). In this study, we have used our recently developed mouse model for AGU and analyzed processing, intracellular localization, and endocytosis of recombinant AGA in telencephalic AGU mouse neurons in vitro. The processing steps of AGA were found to be similar to the peripheral cells, but both the accumulation of the inactive precursor molecule and delayed lysosomal processing of the enzyme were detected. AGA was distributed to the cell soma and neuronal processes but was not found in the nerve terminals. Endocytotic capability of cultured telencephalic neurons was comparable to that of fibroblasts, and endocytosis of AGA was blocked by free mannose-6-phosphate (M6P), indicating that uptake of the enzyme was mediated by M6P receptors (M6PRs). Uptake of extracellular AGA was also studied in the tumor-derived cell lines rat pheochromocytoma (PC12) and mouse neuroblastoma cells (N18), which both endocytosed AGA poorly as compared with cultured primary neurons. Expression of cation-independent M6PRs (CI-M6PRs) in different cell lines correlated well with the endocytotic capability of these cells. Although a punctate expression pattern of CI-M6PRs was found in fibroblasts and cultured primary neurons, the expression was beyond the detection limit in PC12 and N18 cells. This indicates that PC12 and N18 are not feasible cell lines to describe neuronal uptake of mannose-6-phosphate-tagged proteins. This in vitro data will form an important basis for the brain-targeted therapy of AGU.

Key words: aspartylglucosaminidase; aspartylglucosaminuria; lysosomal enzyme; mannose-6-phosphate receptor; primary neurons; mouse

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18197750-07$05.00/0

This article has been cited by other articles:

				M. Lehtovirta, A. Kyttala, E.-L. Eskelinen, M. Hess, O. Heinonen, and A. Jalanko Palmitoyl protein thioesterase (PPT) localizes into synaptosomes and synaptic vesicles in neurons: implications for infantile neuronal ceroid lipofuscinosis (INCL) Hum. Mol. Genet., January 1, 2001; 10(1): 69 - 75. [Abstract] [Full Text] [PDF]

				L. Peltonen, A. Jalanko, and T. Varilo Molecular genetics of the Finnishdisease heritage Hum. Mol. Genet., September 1, 1999; 8(10): 1913 - 1923. [Abstract] [Full Text] [PDF]

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