Investigating the role of neuraminidase 1 in Sanfilippo

The Sanfilippo Children’s Foundation in partnership with Fundacja Sanfilippo (Poland), Sanfilippo Initiative (Germany), and the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud) have awarded an Incubator Grant to Professor Alexey Pshezhetsky at CHU Sainte-Justine, University of Montreal. Prof. Pshezhetsky and his team will investigate whether the secondary deficiency of an enzyme called neuraminidase 1 contributes to the CNS pathology in Sanfilippo.

Sanfilippo syndrome is caused by a deficiency of one of four enzymes: sulfamidase, NAGLU, HGSNAT, or GNS. This primarily leads to an accumulation of heparan sulfate in the brain and body. Currently, the exact steps that lead from this accumulation of heparan sulfate to cell damage and disease symptoms are not completely understood. 

When researching potential disease mechanisms in Sanfilippo disease, Prof. Pshezhetsky and his team found that another enzyme, called neuraminidase 1 (NEU1), is also deficient in Sanfilippo. They proposed that this ‘secondary deficiency’ of NEU1 is contributing to the Sanfilippo disease process.

NEU1’s role in the body is to remove special sugars, called sialic acids, from proteins that are coated with them. It is an important enzyme: changes in the NEU1 gene leading to a primary deficiency of the NEU1 enzyme result in a disease called sialidosis, a severe lysosomal storage disorder like Sanfilippo. 

When Prof. Pshezhetsky’s team studied a Sanfilippo type C mice model, they also found that their brain contains more sialic acid-coated proteins. These findings were mirrored in post-mortem tissues of patients with Sanfilippo. 

In this project, Prof. Pshezhetsky and his team will investigate this secondary NEU1 deficiency further to confirm whether it contributes to the neurological symptoms of Sanfilippo disease.

First, the team will use mice models to see if NEU1 activity is also reduced in other lysosomal diseases, understand the biological processes leading to this secondary deficiency, and better understand the consequences of increased sialic acid-coated proteins for brain function.

“Understanding how Sanfilippo and its symptoms develop is essential for Sanfilippo research and therapy development,” said CEO of the Sanfilippo Children’s Foundation, Victoria Bowring. “Insights gained from this project may inform future therapeutic avenues for Sanfilippo syndrome.”

Alexey Pshezhetsky is a Professor of paediatrics and biochemistry at the University of Montreal and a researcher at Ste-Justine University Hospital Center (CHUSJ). He has over 25 years of experience researching disease mechanisms and developing treatments for genetic diseases that affect children, including Sanfilippo and particularly Sanfilippo type C.

  • Project title: Secondary deficiency of neuraminidase 1 in neurological mucopolysaccharidoses: mechanism and pathological implications
  • Chief investigator: Prof. Alexey Pshezhetsky; collaborators: Prof. Domenico Garozzo (Italy) and Prof. Herbert Hildebrandt (Germany) 
  • Amount: $27,500 from Sanfilippo Children’s Foundation, $18,750 from Fundacja Sanfilippo (Poland), $18,750 from Sanfilippo Initiative (Germany), and $10,000 from the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud)
  • Duration: 1 year
  • Location: CHU Sainte-Justine, University of Montreal
  • Status: Active
  • Start date: May 2022



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