Research finds strategy that may treat juvenile Batten disease
A novel approach to finding a treatment
“A few years back we discovered a protein in cells called TFEB, a master transcription factor that stimulates the cell to produce more lysosomes and degrade cellular waste more effectively,” said Sardiello. “So we thought about counteracting the accumulation of cellular waste in Batten disease by acting on TFEB.”
“We and others had found that enhancing the activity of TFEB genetically can help counter the accumulation of cellular waste in different diseases,” Sardiello said. “What was missing was a way to activate TFEB with a drug that in the future could be put in a pill to treat the condition. We focused on investigating how to activate TFEB pharmacologically.”
“We discovered that TFEB is under the control of another molecule called Akt, which is a kinase, a protein that can modify other proteins,” said Palmieri. “Akt has been studied in detail. There are drugs available that can modulate the activity of Akt.”
The researchers discovered that Akt modifies TFEB by adding a chemical group, a phosphate, to it. This chemical modification inactivates TFEB.
“We wanted to inhibit Akt to keep TFEB more active,” said Palmieri. “We discovered that the sugar trehalose is able to do this job.”
Testing a treatment for juvenile Batten disease in a mouse model of the condition
The scientists tested the effect of trehalose in a mouse model of juvenile Batten disease.
“We dissolved trehalose in drinking water and gave it to mice that model juvenile Batten disease,” said Sardiello. “Then, over time we examined the mice’s brain cells under the microscope. We found that the continuous administration of trehalose inhibits Akt and activates TFEB in the brains of the mice. More active TFEB meant more lysosomes in the brain and increased lysosomal activity, followed by decreased accumulation of the storage material and reduced tissue inflammation, which is one of the main features of this disease in people, and reduced neurodegeneration. These changes resulted in the mice living significantly longer. This is a good start toward finding a treatment for people with this disease.”
“We are very excited that these findings put research a step closer to understanding the mechanisms that underlie human lysosomal storage diseases,” said Palmieri. “We hope that our research will help us design treatments to counteract this and other human diseases with a pathological storage component, such as Alzheimer’s, Huntington’s and Parkinson’s diseases, and hopefully ameliorate the symptoms or reduce the progression of the disease for those affected.”
The following researchers also contributed to this work: Rituraj Pal, Hemanth R. Nelvagal, Parisa Lotfi, Gary R. Stinnett, Michelle L. Seymour, Arindam Chaudhury, Lakshya Bajaj, Vitaliy V. Bondar, Laura Bremner, Usama Saleem, Dennis Y. Tse, Deepthi Sanagasetti, Samuel M. Wu, Joel R. Neilson, Fred A. Pereira, Robia G. Pautler, George G. Rodney and Jonathan D. Cooper.
This work was supported by NIH grant NS079618, grants from the Beyond Batten Disease Foundation, March of Dimes Foundation grant #5-FY12-114, and a King’s College London Graduate School International Studentship. This project was also supported in part by the Hamill Foundation and by IDDRC grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Cores: Mouse Neurobehavior, RNA In Situ Hybridization, and Integrated Microscopy).
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Palmieri, M., et al., “mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases,” Nature Communications, February 2017, DOI: 10.1038/NCOMMS14338.