A new study in Autophagy from the laboratory of Dr. Marco Sardiello, assistant professor in Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, has found oral administration of trehalose, a simple sugar, can alleviate the neurological symptoms associated with the deficiency of a lysosomal enzyme.
Humans and animals deficient in a–N-acetylglucosaminidase (NAGLU) enzyme accumulate toxic amounts of a type of mucopolysaccharide called heparan sulfate. To find alternative therapeutic strategies for this rare genetic disease, researchers administered NAGLU-deficient mice with trehalose to enhance the cells’ ability to clear cellular waste which resulted in a longer life span and improvement in neurological symptoms.
This study opens the doors to develop a viable therapeutic strategy for many human lysosomal storage disorders (LSDs) and other early-onset neurodegenerative disorders.
Currently, researchers are trying several strategies such as enzyme replacement therapy, bone marrow transplantation and gene therapy to treat LSDs. However, these approaches have not been entirely successful due to the limited ability of the enzymes to cross the blood-brain barrier or, for gene therapy, limited capacity of the vectors to transduce all cells in the brain. Also, all of the previously tested methods failed to show any improvement in retinal degeneration or restore vision loss.
Lysosomes are cellular sacs that act as the ‘trash bins’ of the cells. They use enzymes to degrade cellular waste and recycle unwanted or dysfunctional proteins, lipids and sugars. Cells also have another destructive mechanism called ‘autophagy’ that allows for orderly and regulated recycling of cellular components, and is triggered under conditions of stress or starvation.
Cells deficient in lysosomal enzymes or with dysfunctional autophagic pathways accumulate large quantities of cellular waste. Neurons are especially sensitive to these accumulations and undergo massive degeneration, which is believed to be the underlying cause of early-onset neurodegenerative diseases like LSDs as well as late-onset disorders like Alzheimer’s and Parkinson’s.
The Sardiello lab had previously discovered that trehalose activates transcription factor EB (TFEB), a master regulator of the autophagy-lysosomal system and lysosomal exocytosis, a process by which the lysosomes (‘trash bins’) empty their contents to outside the cell.
In this particular study, researchers explored if this alternate non-traditional approach can ameliorate neurological symptoms of LSDs and Sanfilippo syndrome. They enhanced the cell’s natural degradative mechanisms with the premise that more efficient removal of toxic cellular debris may help restore normal neurological function.
Sanfilippo syndrome is one of the LSDs that causes progressive neurodegeneration due to the accumulation of a mucopolysaccharide, heparin sulfate due to the deficiency of NAGLU. Infants with Sanfilippo syndrome exhibit behavioral and cognitive decline, severe dementia, loss of speech, vision and hearing, hyperactivity, and sleep disturbances that progressively worsen to also include seizures, as they get older.
The researchers administered trehalose, a sugar molecule that induces autophagy, to mice that lacked the gene that codes for NAGLU enzyme (naglu-/-) and exhibits similar symptoms as seen in Sanfilippo syndrome (or MSP IIIB) patients. Molecular, neuropathological, functional and behavioral assays were then used to test if this could reverse the symptoms.
First, they were able to show via mass spectrometric analysis that, unlike the enzymes or small-molecules tested earlier, trehalose was indeed able to cross the blood-brain barrier. They found that administration of trehalose significantly increased the life span and reduced hyperactivity/anxiety-related behaviors in these mice. It also restored the hearing ability in a subset of these mice.
Remarkably, retina of trehalose-treated naglu-/- mice had so little retinal degeneration that they were often undistinguishable from retina of normal mice and this was accompanied by improved retinal function. This is the first therapeutic approach to have shown a significant reduction in retinal degeneration and improved vision in MPS IIIB mice.
Further, they showed that efficient clearance was likely the underlying cause of these positive changes in MPS IIIB mice. Trehalose treatment elevated autophagy–lysosomal pathways in the cortex and cerebellum of the brain, regions important for higher cognitive functions and muscular movement respectively as well as in the photoreceptor cells in the retina.
This is the first demonstration of the role of trehalose in ameliorating neurological symptoms caused by the deficiency of an enzyme. It is also encouraging that trehalose is a widely used food additive and is considered generally safe for human use.
The researchers hope that in the future this strategy can potentially be used either as the main therapy or complementary to other therapies to combat neurological symptoms of LSDs. In addition, this approach could potentially also prove beneficial other early-onset neurodegenerative diseases such as Batten disease.