Researchers solve mystery surrounding form of Batten disease
Discovering a new fundamental mechanism
To solve the mystery, the researchers first looked for proteins that would assist on the exit of lysosomal enzymes from the endoplasmic reticulum en route to the 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 worked with mice carrying defective CLN8 molecules, a mouse model that recapitulates many of the characteristics of the disease observed in humans. They determined that in these mice the lysosomes have fewer lysosomal enzymes.
“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.”
In addition, the researchers discovered that a specific piece of CLN8 acts like a hook, ‘catching’ lysosomal enzymes to facilitate their exit from the endoplasmic reticulum. They also identified the molecular signals that help CLN8 move from the endoplasmic reticulum to its destination and back. These discoveries open potential new therapeutic interventions.
“I started this research because I wanted to contribute to improve 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.”
“Co-author Lauren Popp and I were very excited to contribute to this study that elucidated a novel mechanism of lysosomal formation,” said co-author Dr. Laura Segatori, associate professor of chemical and biomolecular engineering at Rice University. “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.”
“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.”
Other contributors to this work include Lakshya Bajaj, Jaiprakash Sharma, Deepthi Sanagasetti, Parisa Lotfi, Carolyn Joy Adamski, John Collette, Michela Palmieri, Abdallah Amawi, Kevin Tommy Chang, María Chiara Meschini, Hon-Chiu Eastwood Leung, Alessandro Simonati, Richard Norman Sifers and Filippo Maria Santorelli. The authors are affiliated with one of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Rice University, University of Verona, Italy and IRCCS Stella Maris, Italy.
This work was supported by the National Institutes of Health grant NS079618 and grants from the Beyond Batten Disease Foundation and the NCL-Stiftung Foundation. This project was supported in part by the Hamill Foundation and by the Intellectual and Developmental Disabilities Research Center grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.