Juvenile Batten disease is a progressive disease that causes neurological dysfunction, resulting in seizures, changes in behavior, blindness, dementia, and a loss of motor skills including the ability to speak. This genetic disorder can vary widely from patient to patient, but often spells an early death for those affected, according to BDSRA, the Batten Disease Support and Research Association. Researchers working at Baylor College of Medicine may have made a breakthrough in understanding this disorder, in which cellular parts called lysosomes do not function properly. In a mouse model of the disease, the Baylor researchers improved the neurological symptoms. The findings are discussed in the video below, and the work was published in Nature Communications.
"Patients with juvenile Batten disease are born healthy and reach the expected developmental milestones of the first 4 to 6 years of age," explained the senior author of this work, Dr. Marco Sardiello, an Assistant Professor of Molecular and Human Genetics at Baylor. "Then, these children progressively regress their developmental achievements; they gradually lose their vision and develop intellectual and motor disabilities, changes in behavior and speech difficulties. Most people with this condition live into their 20s or 30s. This inherited, rare disease has no cure or treatment other than palliative care."
"As we started this project, patients and families affected by this condition visited us in the laboratory," said the study first author Dr. Michela Palmieri, a postdoctoral fellow in the Sardiello lab at the time of this project, and currently with the San Raffaele Scientific Institute in Milan, Italy. "We were deeply affected by our interactions with the patients and their families and this further motivated us to pursue this research with the hope that maybe one day it will lead to a treatment that will improve the lives of people affected by this condition."
Cells aren’t a totally efficient system, and waste products leftover from various cellular functions have to be properly removed or they can cause problems for the cell. When such waste builds up, it can totally disrupt the normal health of the cell. A bit of specialized cellular machinery, an organelle called the lysosome is tasked with cellular waste disposal.
Material that is to be disposed accumulates inside of lysosome, which are filled with degradative enzymes that breaks waste down into pieces that can be easily discarded, or can be recycled for use in other purposes. A breakdown of lysosomes that leaves waste to build up is very unhealthy for cells. While this is detrimental to any cell type, it seems that cells of the brain, neurons, are particularly susceptible to disease as a result of lysosome dysfunction - termed lysosomal storage disorders.
"In juvenile Batten disease, one of nearly 50 human lysosomal storage disorders, the function of brain cells is progressively affected by the accumulation of cellular waste," Sardiello explained. "This accumulation leads to perturbation of many cellular processes, cell death and progressive regression of motor, physical and intellectual abilities. 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, 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 continued. "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," explained Palmieri. "Akt has been studied in detail. There are drugs available that can modulate the activity of Akt."
The investigators found that TFEB is modified by Akt, which adds a chemical group, a phosphate, to the TFEB. That phosphate addition stops the action of 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."
Investigating the result of trehalose exposure in a mouse model of juvenile Batten disease was the next step for the researchers. "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."