The juvenile Batten disease gene
Juvenile Batten disease results from mutations (mistakes) in the CLN3 gene (blueprint) responsible for making CLN3 protein. More than 60 different mutations in the CLN3 gene have been shown to cause juvenile Batten disease.18 However, most children with the disease are missing the same string of 1,000 DNA building blocks from the CLN3 gene; this mutation is known as the “1kb deletion.” The effects of the 1kb deletion are not well-understood, although it is believed that such a large missing piece of the blueprint for CLN3 means cells aren’t making any functional CLN3 protein.
Where is CLN3 protein supposed to be?
CLN3 protein is found in the membranes (walls) of various cellular compartments (organelles), all of which serve different functions – like rooms in a house. CLN3 protein is found in the membrane surrounding the part of the cell that modifies proteins (Golgi apparatus), the part that stores energy for the cell (mitochondria), transporter organelles (endosomes), the nuclear envelope responsible for regulating what enters and leaves the nucleus, the outer cell membrane and the cell’s recycling center (lysosomes). 9-13, 20, 21 In neurons, CLN3 protein can be found in special compartments called synaptosomes, structures that are important for communication between nerve cells. 13, 14 CLN3 may have the same function in every compartment of a cell, different functions in each, or a mixture.
What is CLN3 protein doing in all of these places?
The accumulation of undigested waste material in the garbage disposal and recycling centers (lysosomes) of the cell is the pathological hallmark of lysosomal storage diseases like Batten. At first, researchers believed this buildup was toxic and that removing it could stop disease progression. However, affected brain regions show signs of damage that does not correlate with the amount of storage material that has accumulated. Studies have also shown that actively removing waste material does not inhibit infantile Batten (CLN1) disease progression.7, 8, 22, 23
In addition to waste disposal, lysosomes are rapidly being recognized for their role in cell-to-cell communication, membrane repair, protein transport, and maintaining the cell’s equilibrium. 8, 13-16, 17, 18 Studies have also shown that lysosomal disturbances have a profound impact on the health of neurons in more well-known neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases. 1, 2, 3 Neurons may be especially sensitive to fluctuations in these processes and the overall equilibrium of the cell. While brain cells can compensate for missing CLN3 protein for a short time, eventually the scales tip too far and they begin to break down.
How do we figure out what CLN3 protein does? More importantly, how do we fix the problems that occur when functional CLN3 protein is missing?
University-based researchers are hard at work using the latest molecular techniques and animal models to 1) confirm the functions of CLN3 protein, 2) identify which CLN3 protein functions are most critical to the cell’s overall health and functioning, and 3) identify ways to fix the earliest and most damaging effects of the loss of CLN3 protein. At the same time, scientists practicing clinical and translational research in the pharmaceutical sector are working to transform these discoveries into treatments for Batten disease. It is estimated that it takes an average of $1.3 billion and 12 years to turn a discovery into medicine to treat a disease. 4, 5, 6 To see an animation of our strategic path toward a cure, click here. To watch our latest webinar, click here. To see a list of specific research investments, see our research pages.