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.
Highlights
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
They manifest in other forms of mucopolysaccharidosis (MPS) characterized by defective metabolism of heparan sulfate (HS), such as MPS-II and MPS-I, caused by disruptions to the enzymes iduronate-2sulfatase and α-L-iduronidase, respectively, which leads to accumulation of HS and other GAGs; for this reason, these diseases are accompanied by a faster shift from autistic- to dementia-like symptoms, meaning autistic-like symptoms can be harder to detect[5,6]
To dissociate early behavioural from late-occurring dementia-like behaviours, we focused on the analysis on 2-month-old MPS-IIIA and WT littermate mice (Fig. 1, light blue bars) which, based on our previous studies, have not yet developed lysosomal/autophagosome dysfunctions, inflammation and secondary storages[25]
Summary
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. 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. Typical and atypical antipsychotics, such as haloperidol and risperidone, are dopaminergic drugs thought to exert their effects by inhibiting the action of dopamine (DA) projections, originating in the mesencephalon, on D2 receptors (D2Rs) in the prefrontal cortex and the striatum They have few or variable therapeutic effects on autistic-like behaviours in MPS-IIIA, with most success against hyperactivity in very young children; they have been reported to have considerably higher than expected extrapyramidal side effects in older patients[7,8,9], which suggests diseasespecific alterations in the dopaminergic systems of MPS-IIIA patients. The impact of the impairment of HS signalling on the regulation of the dopaminergic system and, on autistic behaviours in MPS-III is currently not understood
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