The juvenile Batten disease gene
Juvenile Batten disease results from mutations (mistakes) in the CLN3 gene (blueprint) responsible for making CLN3 protein. More than Sixty-seven (67) different mutations in the CLN3 gene have been shown to cause juvenile Batten disease(Mole). However, most children with the disease are missing a string of 966 DNA building blocks in one or both of their mutated CLN3 genes. This is known as the “～1kb deletion.” The specific effects of the ～1kb deletion or other 66 disease-causing mutations are not well-understood. However, it is believed that cells with mutations in both of their CLN3 genes do not make fully functional CLN3 protein. (Katz, Gao et al. 1997)
Where is CLN3 protein supposed to be?
CLN3 protein is found in the membranes (walls) of various cellular compartments (organelles). Much like a bustling city with departments for utilities and transportation, organelles have different functions working together to support the overall health of the cell. There are power plants (mitochondria), processing and packaging centers (Golgi apparatus), transit centers (endoplasmic reticulum), and the sanitation department (lysosomes)(Jarvela, Sainio et al. 1998, Luiro, Kopra et al. 2001, Luiro, Kopra et al. 2006)(Kyttala, Ihrke et al. 2004)(Katz, Gao et al. 1997, Kremmidiotis, Lensink et al. 1999, Pearce 2000, Persaud-Sawin, McNamara et al. 2004, Phillips, Benedict et al. 2005)CLN3 protein has been found in the membranes of all of these organelles as well as the nuclear envelope, responsible for regulating what enters and leaves the nucleus(Luiro, Kopra et al. 2001, Luiro, Kopra et al. 2006). In neurons, CLN3 protein can be found in specialized compartments called synaptosomes which are important for communication between nerve cells. CLN3 protein may have the same function in each of these organelles or different functions depending on the cell’s needs. Although we don’t know the true function(s) of the protein, there are several clues.
What is CLN3 protein doing in all of these places?
The accumulation of undigested autofluorescent waste material in the garbage disposal and recycling center (lysosomes) of cells is the clinical hallmark of juvenile Batten disease suggesting that CLN3 protein plays a critical role in lysosomal function. The presence of CLN3 within other organelles could represent interactions between lysosomes and those organelles and/or it is possible that CLN3 plays a minor role in non-lysosomal sites.
In addition to waste removal and recycling, lysosomes are important for sensing and maintaining a cell’s nutrient status, cell-to-cell communication, membrane repair, and protein transport system(Luiro, Kopra et al. 2001, Luiro, Yliannala et al. 2004, Luiro, Kopra et al. 2006, Gavin, Wen et al. 2013)(Narayan, Rakheja et al. 2006, Maxfield FR 2016). Studies have also shown that disturbances in these activities have a profound impact on the health of neurons in more well-known neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases(Andrews 2000, Andrews 2005, Metcalf, Calvi et al. 2008, Appelqvist, Waster et al. 2013). Altogether, these results suggest that brain cells (neurons) are especially sensitive to disturbances or changes in lysosomal processes and missing normal CLN3 protein makes them even more vulnerable. They can compensate for the loss of healthy CLN3 for a short time but eventually, the scales tip too far and brain cells begin to die.
We know that CLN3 is a transmembrane protein. A transmembrane protein is an integral protein that spans organelle membranes in a single or multiple pass similar to fabric stitches. Many transmembrane proteins function as gateways permitting specific substances to enter or leave the organelle. Below is a short list of known transmembrane protein functions. We do know which, if any, of these functions can be attributed to CLN3 protein and several laboratories are reporting progress in this area.
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 a variety of state-of-the-art techniques and animal models to 1) pinpoint the function(s) of CLN3 protein, 2) prioritize which CLN3 protein functions are most critical to the cell’s overall health and proper function, and 3) pair their findings with strategies to prevent 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 discoveries made using cell cultures and animal models into safe and effective treatments for children with 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(DiMasi JA 2003, Dickson and Gagnon 2004, HG 2007). To see an animation of our strategic path towards a cure, click here. To see a list of current treatment strategies under investigation, click here.
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