A research team at Baylor College of Medicine has found a surprising mechanism behind neural ceroid lipofuscinosis 8, a form of Batten disease. The research has been recently published in the journal Nature Cell Biology. Understanding this mechanism can help the researchers to set new treatment goals for this rare and incurable disease.
“Batten disease refers to a group of diseases that are part of the lysosomal storage disorders. At the core of these conditions are problems with the cell’s ability to clear the waste produced by its regular functions, which leads to the accumulation of cellular waste to toxic levels,” said first author Dr. Alberto di Ronza, who was a postdoctoral researcher in the Sardiello lab while he was working on this project.
Lysosomes are the special structures in the body which are responsible for clearing the waste of the body. They have a sac-like appearance and contains proteinaceous enzymes which are in charge of breaking down the cellular debris into the simple constituents that can be later on recycled or removed by the body. When lysosomes fail to perform their function, the disease starts to develop itself.
“When we started this project, we knew that neuronal ceroid lipofuscinosis 8 was associated with defects in the CLN8 protein, but we didn’t know how the defects led to the disease,” said corresponding author Dr. Marco Sardiello, assistant professor of molecular and human genetics at Baylor.
It is quite surprising as CLN8 is not found in the lysosome. It performs its function in a different part of the body, that is endoplasmic reticulum. The endoplasmic reticulum is an organelle where many molecules, as well as the lysosomal enzyme, is synthesized. The thing which made the researchers shocked was that how mutations in CLN8 caused a lysosomal storage disorder when it is not located in the lysosome.
To resolve the issue, the researchers studied hard to know the proteins which help the lysosomal enzymes exit the endoplasmic reticulum and enter lysosomes.
“We narrowed it down to four candidates and CLN8 was one of them. It was the only one that interacted with two-thirds of the lysosomal enzymes we tested,” di Ronza said.
Then the researchers carried out their study in mice, the one who had defective CLN8 molecules as mice and humans have almost the same characteristics of diseases. What they found was that in these mice there are fewer enzymes in the lysosomes.
“Things started to click,” Sardiello said. “If CLN8 in the endoplasmic reticulum-mediated transfer of lysosomal enzymes, then having defective CLN8 proteins could explain why fewer enzymes make it to the lysosome.”
The researchers found that a part of CLN8 bears a hook which helps in exiting the lysosomal enzymes from the endoplasmic reticulum. There were some molecular signals which facilitated the movement of CLN8.
“I started this research because I wanted to contribute in improving patients’ lives,” di Ronza said. “Patients with CLN8 defects have limited options, but I hope that this work will provide opportunities to explore potential new therapies for these patients.”
“Our group has focused on understanding and manipulating the mechanisms controlling processing of lysosomal proteins. I am excited that this study provides novel findings that are likely to change the way we approach the study and treatment of lysosomal storage disorders,” said co-author Dr. Laura Segatori, associate professor of chemical and biomolecular engineering at Rice University.
“The solution to this mystery was completely unexpected,” Sardiello said. “We identified a new fundamental biological process that, when is disturbed, leads to this form of lysosome storage disease. This discovery is relevant not only to the Batten disease community but also to other scientific communities studying basic mechanisms of the cell.”