Research: Lysosomal storage disorders with altered heparan sulfate metabolism lead to dopamine-dependent autistic behaviors in Sanfilippo mouse models

June 28, 2021

A research project co-funded by Cure Sanfilippo Foundation and Sanfilippo Children’s Foundation (Australia) recently published its findings, “Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders,” in the June edition of Nature Communications.

“This work sheds light on a critical but historically understudied area – mechanisms behind the autism-related behaviors common in Sanfilippo,” said Dr. Cara O’Neill, Chief Science Officer for Cure Sanfilippo Foundation. “It also offers directly translatable information for patients and their doctors searching for guidance on medications to address behavioral symptoms. We are honored to support this work and look forward to future studies from the team to understand and address defects in the dopamine system across the lifespan in Sanfilippo.”

The paper notes that the autistic behaviors seen in children with all types of MPS III (Sanfilippo syndrome, Types A, B, C, and D) also manifest in other MPS disorders which accumulate abnormal forms of heparan sulfate (MPS I-Hurler and MPS II-Hunter).

“Understanding the disease mechanisms leading to autism in MPS-III is highly relevant in the field of ASD (autism spectrum disorder), since HS function is an integral part of the core synaptic organizing complexes neurexin and neuroligin, whose genes (NRXN and NLGN, respectively) are mutated in autism,” noted the article.

“Targeting autistic-like symptoms represents an urgent unmet clinical need in MPS-IIIA patients, which show social and affective abnormalities, hyperactivity, repetitive behavior and restricted rituals and routines (such as repetitive motor stereotypies and sensory interests). Some autistic-like behaviors have already been described in MPS-IIIA mice; however, a full characterization has not been performed and the disease mechanisms that underpin this disease are yet to be identified,” stated the article’s authors.

Study Design

The study used the Sgsh−/− mouse model to investigate changes in the development and function of the meso-striatal dopaminergic system in MPS-IIIA and sensitivity to dopaminergic drugs. Using different in vitro models of MPS-IIIA (primary mesencephalic neurons, induced dopaminergic neurons and neuroblastoma cell line knocked-out for the gene SGSH by CRISPR/Cas9), the study tested the role of HS in regulating dopaminergic dysfunction in MPS-IIIA.

Study Findings

The study reported that “autistic behaviors preceded dementia-like behaviors in MPS IIIA mice.”

Studying MPS IIIA male mice, it was observed that the shift from autistic- to dementia-like behaviors was progressive. The 2-month-old mice were hyperactive and demonstrated stereotyped autistic behaviors and social responses. The 8-month-old mice were hypoactive and showed no significant stereotyped behavior or social interaction deficits. The 6-month-old mice demonstrated a mixed set of behavioral impairments.

Other key findings reported from the study:

  • Autistic-like behavior in Sanfilippo Type A (MPS-IIIA) is due to striatal hyperdopaminergia and is rescued by the D1-like receptor antagonist (SCH-23390) but not the D2- like receptor antagonist haloperidol
  • Hyperdopaminergia in MPS-IIIA is due to increased proliferation of dopamine cells originating during embryonic development
  • Increased proliferation of dopamine cells does not occur in parallel with lysosomal dysfunction; therefore, we hypothesized that it was due to the altered function of HS.
  • SH-SY5Y CRISPR/Cas9 MPS-IIIA cell line model shows increased proliferation of dopamine cells, which is reduced by the application of typical functional heparan sulfate
  • Hyperdopaminergia and autistic behaviors also manifest in the MPS-II mouse model

“Our findings report a proof-of-concept, pre-clinical evidence on the use of D1R antagonists to treat autistic-like behaviors in MPS-IIIA,” stated the article. “Furthermore, the autistic-like behaviors and dementia-like stages can be phenotypically dissociated in terms of behavioral patterns and dopaminergic status, suggesting that parallel disease mechanisms might concurrently lead to autistic-like and dementia-like symptoms in MPS-IIIA.”


De Risi, M., Tufano, M., Alvino, F.G. et al.Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders. Nat Commun 12, 3495 (2021).

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