A research study by Professor Grzegorz Wegrzyn and his team from the University of Gdansk, Poland, has described how the cell cycle is affected in Sanfilippo and other mucopolysaccharidoses (MPS disorders).
Sanfilippo, also known as MPS III, is one of seven MPS disorders that all involve the build-up of complex sugar molecules called glucosaminoglycans (GAGs). Different types of GAG molecules accumulate depending on the type of MPS, but in Sanfilippo, the primary molecule involved is heparan sulfate. The build-up of GAGs affects other processes in the body, contributing to the severity of the disease.
In the study, the researchers wanted to see how high levels of GAGs in MPS disorders impact the cell cycle, a complex process controlling the growth and division of cells. To do this, they used skin cells from 11 different MPS patients, including one cell line for each Sanfilippo subtype (A, B, C, and D).
To maintain the tissues of the body, most cells in the body go through cycles of growth followed by division to generate new cells. The team looked at the timing of different cell cycle phases of the cell lines as they grew in dishes in the laboratory. They found disturbances in the timing of the cell cycle stages in all of the MPS skin cells, with fewer cells found to be in the final division phase.
The researchers also looked at the activity of genes involved in the cell cycle in the MPS cells compared to unaffected cells. Eighteen genes showed altered activity in at least six different MPS types. Many of these changes appeared consistent between different MPS disorders, leading the researchers to conclude that the high GAG levels in the different MPS disorders may cause cell cycle defects via a similar mechanism.
The team focused on a group of proteins called cyclins, which are critical in regulating the cell cycle. In particular, they saw irregular timing and increased levels of cyclin D1 activity in many MPS types, including in Sanfilippo type A, C, and D cells. As a result, they proposed drugs targeting cyclin D1 as a potential therapeutic avenue for MPS disorders in combination with other therapies.
The team also tested if enzyme replacement therapy or substrate reduction therapy could correct the cell cycle dysfunction in the MPS skin cells. When the GAG levels were reduced by either of these methods, improvements were seen, but the cell cycle did not return to normal.
This study presents another example of how high levels of GAGs can affect other critical processes in the cell, causing secondary effects that worsen MPS disease. While the study looks at the impact on the cell cycle in MPS, it is uncertain whether drugs targeting the cell cycle would halt or improve neurodegeneration in Sanfilippo. This is because mature neurons do not undergo cell division; each neuron must survive throughout a person’s lifetime. However, treatments targeting the cell cycle may help to improve other non-neurological symptoms seen in Sanfilippo and other MPS disorders.
The project was made possible with a grant from the National Science Center, Poland.