Emerging pathways of neurodegeneration in Sanfilippo syndrome

Sanfilippo syndrome (also called MPS-IIIA-D) is due to the loss of the gene that codifies for sulfamidase, a lysosomal enzyme that degrades the glycosaminoglycan (GAG) heparan sulfate (HS). The lysosome is responsible for cell clearance of misfolded proteins and physiological catabolism of cell components such as GAGs. In MPS-IIIA, undegraded HS accumulates in the lysosome, progressively engulfing it and damaging its degradative capacity, leading to the accumulation of secondary storages composed of misfolded proteins such as alpha-synuclein, tau and beta-amyloid; the latter are protein aggregates responsible for neurodegeneration in age-related neurodegenerative disorders. The loss of function of the lysosome is therefore considered as the primary cause of neurodegeneration in MPS-IIIA, responsible for the dementia that occurs at the latest stage of the disease.

HS is a sulfated polysaccharide that has many physiological functions in the brain. HS not only acts as co-receptor of many growth factors, which are important not only during brain development, but is also involved in the processes leading to beta-amyloid and tau protein aggregation. Although, previous studies had shown a loss of function of HS in MPS, a lysosome-centric view of MPS-IIIA has limited the exploration of all its functional consequences in the cell.

Encouraged by our novel and promising preliminary data, we want to dissect the role of altered HS in neurodegeneration in MPS-IIIA. We are confident that this project will bring a novel disease’ modifiers to slow down neurodegeneration and dementia in MPS-IIIA.