# Neuroinflammation as a Novel Therapeutic Frontier for Sanfilippo Syndrome

## TL;DR

This paper explores how neuroinflammation caused by heparan sulfate accumulation could be a new target for treating Sanfilippo Syndrome, a severe inherited neurodegenerative disease.

## Contribution

The paper introduces neuroinflammation as a novel therapeutic target in Sanfilippo Syndrome by linking heparan sulfate accumulation to innate immune activation.

## Key findings

- Heparan sulfate accumulation in lysosomes activates the NLRP3-inflammasome in microglia and astrocytes.
- This activation leads to pro-inflammatory cytokine release and compromised neuron survival.
- Interleukin-1 is identified as a key driver of neuroinflammation in Sanfilippo Syndrome.

## Abstract

Glycosaminoglycans (GAGs), also named ‘mucopolysaccharides’, are nodal constituents of the connective tissue matrix which go through synthesis, demolition, and reconstruction within several cellular structures: an abnormal GAG catabolism is the basis of progressive intra-lysosomal accumulation of non-metabolized GAGs, defining all mucopolysaccharidoses (MPS), protean disorders characterized by physical abnormalities and multi-organ failure depending on the specific site of non-renewable GAGs stored. A severe cognitive decline is typically observed in the Sanfilippo syndrome, which corresponds to MPS type III, a group of four inherited neurodegenerative diseases resulting from the lack of specific enzymes involved in heparan sulfate (HS) metabolism. As a consequence, the storage of partially degraded HS fragments within lysosomes of the central nervous system elicits chain inflammatory reactions involving the NLRP3-inflammasome in microglia and astrocytes, which cease their homeostatic and immune functions and finally compromise neuron survival. This article provides an overview of the neuroinflammatory picture observed in children with MPS type III, postulating a role of HS accumulation to prime innate immunity responses which culminate with pro-inflammatory cytokine release in the brain and highlighting the relevance of interleukin-1 as a main contributor to neuroinflammation.