These authors contributed equally to this work.
Loss of the Batten Disease Gene CLN3 Prevents Exit from the TGN of the Mannose 6-Phosphate Receptor
Article first published online: 4 AUG 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Munksgaard
Volume 9, Issue 11, pages 1905–1914, November 2008
How to Cite
Metcalf, D. J., Calvi, A. A., Seaman, M. N., Mitchison, H. M. and Cutler, D. F. (2008), Loss of the Batten Disease Gene CLN3 Prevents Exit from the TGN of the Mannose 6-Phosphate Receptor. Traffic, 9: 1905–1914. doi: 10.1111/j.1600-0854.2008.00807.x
- Issue published online: 10 OCT 2008
- Article first published online: 4 AUG 2008
- Received 28 June 2008, revised and accepted for publication 31 July 2008, uncorrected manuscript published online 4 August 2008
- mannose 6-phosphate;
- neuronal ceroid lipofuscinosis;
The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of inherited childhood-onset neurodegenerative disorders characterized by the lysosomal accumulation of undigested material within cells. To understand this dysfunction, we analysed trafficking of the cation-independent mannose 6-phosphate receptor (CI-MPR), which delivers the digestive enzymes to lysosomes. A common form of NCL is caused by mutations in CLN3, a multipass transmembrane protein of unknown function. We report that ablation of CLN3 causes accumulation of CI-MPR in the trans Golgi network, reflecting a 50% reduction in exit. This CI-MPR trafficking defect is accompanied by a fall in maturation and cellular activity of lysosomal cathepsins. CLN3 is therefore essential for trafficking along the route needed for delivery of lysosomal enzymes, and its loss thereby contributes to and may explain the lysosomal dysfunction underlying Batten disease.