Defects in Autophagy Underlie Eye Symptoms in Sanfilippo Type A, Mouse Study Shows

An abnormal accumulation of heparan sulfates — a hallmark of Sanfilippo syndrome type A — in the retina causes cell death and induces eye symptoms by impairing a process called autophagy, which cells use to clear out unwanted components, a study of mice has found.

Notably, eye symptoms developed before signs of central nervous system (CNS) impairment were evident, suggesting that retinal assessments may help diagnose the condition earlier.

The study, “Retinal Degeneration in MPS-IIIA Mouse Model,” was published in the journal Frontiers in Cell and Developmental Biology.

Mucopolysaccharidosis (MPS) disorders are identified by deficiencies in lysosomal enzymes involved in the degradation of large sugar molecules called glycosaminoglycans (GAGs).

The most common form of MPS, Sanfilippo syndrome type A, or MPS IIIA, is characterized by a deficiency in the enzyme sulfamidase, causing a buildup of GAG molecules called heparan sulfates.

The disease affects predominantly the brain and spinal cord, causing severe and rapid intellectual deterioration, but eye problems also are common in these patients. How these eye symptoms develop, however, is not fully understood.

A team of researchers in Italy had found that autophagy, the process by which cells eliminate faulty or unnecessary components, is impaired in the CNS of a mouse model of Sanfilippo syndrome type A, leading to inflammation in the brain that culminates in the death of these animals.

Now, the same team set out to investigate if MPS-IIIA mice, which largely resemble humans in terms of disease mechanisms and behavioral problems,  also mirrored patients’ ocular symptoms, and if so, whether authophagy  played a role.

The team found that at 3 months of age, when CNS symptoms were not yet evident, MPS-IIIA mice already showed signs of degeneration in the photoreceptor cells in the retina compared with healthy animals of the same age.

This degeneration continued to progress over time, causing strong vision impairments that culminated at 9 months of age, when CNS symptoms were already severe.

Investigators then demonstrated that photoreceptor degeneration was mostly a consequence of increased inflammation in the retina, which caused photoreceptor cells to die. These processes also were evident at 3 months for age.

An additional round of experiments showed that heparan sulfates were accumulating in the retina of MPS-IIIA mice at early stages, impairing the autophagy process in a similar fashion as had been demonstrated in the CNS of these animals.

This inability to clear out potentially toxic molecules triggered an inflammatory cascade that caused the degeneration of photoreceptor cells.

Overall, the findings “confirmed the block of autophagy pathway and protein degradation impairment in the retina as observed in the CNS of MPS-IIIA mouse model,” and “contribute in uncovering of the role of HS accumulation in photoreceptor survival and function,” the researchers wrote.

They also suggests that, because retinal problems seem to be caused by similar mechanisms as  CNS symptoms in these animals, retinal measures may help develop and assess therapeutic approaches aimed at improving the cognitive problems of Sanfilippo syndrome type A.