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Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of
Maria De Risi1,2, Michele Tufano1, Filomena Grazia Alvino1
1Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
Insights
Altered heparan sulfate (HS) function in lysosomal storage disorders causes autistic-like behaviors in children due to overactive dopamine neurons. A dopamine D1-like receptor antagonist reversed these symptoms in mouse models.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Lysosomal storage disorders, such as Mucopolysaccharidosis (MPS) types II and IIIA, involve heparan sulfate (HS) metabolism defects.
- These disorders lead to neurodegeneration, dementia, and therapy-resistant autistic-like symptoms in children, with the underlying cause of these behaviors being unclear.
Purpose of the Study:
- To investigate the cause of autistic-like behaviors in MPS-II and MPS-IIIA.
- To identify potential therapeutic targets for these symptoms.
Main Methods:
- Utilized mouse and cellular models of MPS-IIIA.
- Analyzed mesencephalic dopamine neuron proliferation during embryogenesis.
- Assessed the effects of dopamine receptor antagonists (SCH-23390 and haloperidol) on autistic-like behaviors and hyperdopaminergia.
Main Results:
- Autistic-like behaviors in MPS-IIIA models stem from increased proliferation of embryonic mesencephalic dopamine neurons, linked to altered HS function, not lysosomal dysfunction.
- Hyperdopaminergia and associated autistic-like behaviors were ameliorated by the dopamine D1-like receptor antagonist SCH-23390.
- The D2-like antagonist haloperidol showed minimal therapeutic effect.
Conclusions:
- Altered HS function during embryonic development causes dopaminergic neurodevelopmental defects, leading to autistic-like behaviors in MPS-II and MPS-IIIA.
- Targeting dopamine D1-like receptors presents a promising therapeutic strategy for these neurodevelopmental symptoms in MPS patients.
Abstract:
Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.
Related Concept Videos
01:22Lysosomal Hydrolases
01:19Autism Spectrum Disorder
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