CHANGE OF THE CYTOSKELETON IN THE MPS III CELLS AND AUTOPHAGY

Project: Changes in the cytoskeleton of MPS III cells, and combination of autophagy with inhibition of glycosaminoglycan synthesis in Sanfilippo disease therapy, Profesor Grzegorz Węgrzyn, Uniwersity of Gdanski, Poland

Description

It was suggested previously that accumulation of hyperphosphorylated tau protein (P-tau) may be an important contribution to pathogenesis of mucopolysaccharidoses (MPS). Preliminary results indicate that there are significant changes in the cytoskeleton of MPS III (Sanfilippo disease) cells which may also cause MPS-related symptoms. It is possible that in the organism at the advanced stage of the disease, efficient elimination of glycosaminoglycans’ (GAG) storage and prevention of their further accumulation might be still insufficient to reverse changes caused by accumulation of P-tau and changes in the cytoskeleton. Therefore, it is likely that for efficient therapy it is crucial to combine a method for elimination of GAG storage with an effective lowering of P-tau and correction of the cytoskeleton. Potentially, such effects could be achieved by employing compounds that stimulate autophagy and at the same time are safe for the organism. Therefore, in this project we will test combinations of genistein (which reduces GAG levels and is also an autophagy stimulator) with various compounds that activate autophagy by the mechanisms different than genistein. We assume that such a method might be more effective that the use of each of compounds separately. We will start with a few molecules, and depending on the results, we will proceed with these combinations (if they are effective) or search for other compounds (if efficiency is not satisfactory). The first group of tested compounds (to be used in combination with genistein) will include: resveratrol (an inhibitor of mTORC1, a negative regulator of autophagy), trehalose (an activator of AMPK, the protein taking part in the signal transduction process that activates autophagy), and curcumin (a compound stabilizing lysosomal membrane, thus making lysosomes and autophagosomes more efficient).

How does the project help patients?

Preliminary results indicate that there are significant changes in the cytoskeleton of MPS III (Sanfilippo disease) cells which may also cause MPS-related symptoms. It seems that accumulation of other than GAGs substances may contribute to the cell degeneration.  Therefore, a method for elimination of GAG storage with an effective lowering of P-tau and correction of the cytoskeleton may be more effective treatment than only elimination of GAG storage.

Chief investigator: Prof. Grzegorz Wegrzyn
Project title: Changes in the cytoskeleton of MPS III cells, and combination of autophagy with inhibition of glycosaminoglycan synthesis in Sanfilippo disease therapy
Location: University of Gdansk, Poland
Status: Active
Start date: September 2017