18 September, 2008. A traffic jam in juvenile NCL (CLN3) 

A recent study from University College London sheds new light on what happens inside cells in juvenile Batten disease (JNCL). The teams of Dr Hannah Mitchison (UCL Institute of Child Health) and Professor Dan Cutler (at the MRC Laboratory for Molecular Cell Biology's Cell Biology Unit, UCL) worked together to propose a novel mechanism for the cause of juvenile Batten disease. 

 Juvenile Batten disease arises from loss of function of the CLN3 gene, and the teams mimicked the effects of the disease using ‘CLN3 knockdown’ to block the CLN3 protein from being made in cells. Normally cells use digestive enzymes in the lysosome to break down waste materials no longer wanted by the cell. In this way lysosomes usually act as the cell’s waste disposal units, but in JNCL this process goes wrong. It was found that this is because the machinery that delivers digestive enzymes to the lysosome no longer works properly. A key molecule that carries these enzymes - the CI-MPR receptor - does not arrive at the lysosome, but gets stuck en route.

The CI-MPR receptor normally ferries its cargo of digestive enzymes from another compartment inside cells to the lysosome. But after ‘CLN3 knockdown’ the CI-MPR receptor and its cargo can’t leave its starting point, so the lysosome doesn’t have its full digestive capability.  Brain cells (neurons) would likely be particularly vulnerable to such a lysosomal crisis, and this could well contribute to the neuronal cell death that happens in JNCL.

More work is now needed to understand exactly how and why the CI-MPR receptor gets stuck following CLN3 dysfunction, and finding ways to free up this blockage may lead to new ways to combat juvenile Batten disease.

Further reading:

DJ Metcalf, AA Calvi, MNJ Seaman, HM Mitchison, DF Cutler. Altered trafficking of a mannose 6-phosphate receptor can explain how loss of CLN3 causes Batten disease. Traffic, in press.  

Click here to download the full PDF file